Tricyclic aromatic and bis-phenyl sulfinyl derivatives

ABSTRACT

The present invention provides compounds of the structure:  
                 
wherein the constituent members are defined herein, including pharmaceutical compositions thereof and methods of treating diseases therewith.

FIELD OF THE INVENTION

The present invention is related to chemical compositions, processes forthe preparation thereof and uses of the composition. Particularly, thepresent invention relates to compositions that include substitutedthioacetamides, and their use in the treatment of diseases, such asexcessive sleepiness, promotion and/or improvement of wakefulness(preferably improvement of wakefulness in patients with excessivesleepiness associated with narcolepsy, sleep apnea (preferablyobstructive sleep apnea/hypopnea) and shift work disorder), treatment ofParkinson's disease, Alzheimer's disease, cerebral ischemia, stroke,eating disorders, attention deficit disorder (“ADD”), attention deficithyperactivity disorder (“ADHD”), depression, schizophrenia, fatigue(preferably fatigue associated with cancer or neurological diseases,such as multiple sclerosis and chronic fatigue syndrome), stimulation ofappetite and weight gain and improvement of cognitive dysfunction.

BACKGROUND OF THE INVENTION

The compounds disclosed herein are related to the biological andchemical analogs of modafinil. Modafinil, C₁₅H₁₅NO₂S, also known as2-(benzhydrylsulfinyl) acetamide, or2-[(diphenylmethyl)sulfinyl]acetamide, a synthetic acetamide derivativewith wake-promoting activity, has been described in French Patent No. 7805 510 and in U.S. Pat. No. 4,177,290 (“the '290 patent”). It has beenapproved by the United States Food and Drug Administration for use inthe treatment of excessive daytime sleepiness associated withnarcolepsy. Methods for preparing modafinil and several derivatives aredescribed in the '290 patent. The levorotatory isomer of modafinil,along with additional modafinil derivatives are described in U.S. Pat.No. 4,927,855, and are reported to be useful for treatment ofhypersomnia, depression, Alzheimer's disease and to have activitytowards the symptoms of dementia and loss of memory, especially in theelderly.

Modafinil has also been described as a useful agent in the treatment ofParkinson's disease (U.S. Pat. No. 5,180,745); in the protection ofcerebral tissue from ischemia (U.S. Pat. No. 5,391,576); in thetreatment of urinary and fecal incontinence (U.S. Pat. No. 5,401,776);and in the treatment of sleep apneas and disorders of central origin(U.S. Pat. No. 5,612,379). In addition, modafinil may be used in thetreatment of eating disorders, and to promote weight gain or stimulateappetite in humans or animals (U.S. Pat. No. 6,455,588), and in thetreatment of attention deficit hyperactivity disorder (U.S. Pat. No.6,346,548), and fatigue, especially fatigue associated with multiplesclerosis (U.S. Pat. No. 6,488,164). U.S. Pat. No. 4,066,686 describesvarious benzhydrylsulphinyl derivatives as being useful in therapy fortreating disturbances of the central nervous system.

Several published patent applications describe derivative forms ofmodafinil and the use of modafinil derivatives in the treatment ofvarious disorders. For example, PCT publication WO 99/25329 describesvarious substituted phenyl analogs of modafinil as being useful fortreating drug-induced sleepiness, especially sleepiness associated withadministration of morphine to cancer patients. U.S. Pat. No. 5,719,168and PCT Publication No. 95/01171 describes modafinil derivatives thatare useful for modifying feeding behavior. PCT Publication No. 02/10125describes several modafinil derivatives of modafinil, along with variouspolymorphic forms of modafinil.

Additional publications describing modafinil derivatives include U.S.Pat. No. 6,492,396, and PCT Publ. No. WO 02/10125.

Terauchi, H, et al. described nicotinamide derivatives useful as ATP-aseinhibitors (Terauchi, H, et al, J. Med. Chem., 1997, 40, 313-321). Inparticular, several N-alkyl substituted 2-(Benzhydrylsulfinyl)nicotinamides are described.

U.S. Pat. Nos. 4,980,372 and 4,935,240 describebenzoylaminophenoxybutanoic acid derivatives. In particular, sulfidederivatives of modafinil containing a phenyl and substituted phenyllinker between the sulfide and carbonyl, and a substituted aryl in theterminal amide position, are disclosed.

Other modafinil derivatives have been disclosed wherein the terminalphenyl groups are constrained by a linking group. For example, in U.S.Pat. No. 5,563,169, certain xanthenyl and thiaxanthenyl derivativeshaving a substituted aryl in the terminal amide position are reported.

Other xanthenyl and thiaxanthenyl derivatives are disclosed in Annis, I;Barany, G. Pept. Proc. Am. Pept. Symp. 15^(th) (Meeting Date 1997)343-344, 1999 (preparation of a xanthenyl derivative of Ellman'sReagent, useful as a reagent in peptide synthesis); Han, Y.; Barany, G.J. Org. Chem., 1997, 62, 3841-3848 (preparation of S-xanthenyl protectedcysteine derivatives, useful as a reagent in peptide synthesis); andEl-Sakka, I. A., et al. Arch. Pharm. (Weinheim), 1994, 327, 133-135(thiaxanthenol derivatives of thioglycolic acid).

Thus, there is a need for novel classes of compounds that possess thebeneficial properties similar to that of modafinil. It has beendiscovered that a class of compounds, referred to herein as substitutedthioacetamides, are useful as agents for treating or preventing variousdiseases or disorders disclosed herein.

SUMMARY OF THE INVENTION

The present invention in one aspect is directed to novel compounds whichare useful in the treatment of diseases, such as excessive sleepiness,promotion and/or improvement of wakefulness (preferably improvement ofwakefulness in patients with excessive sleepiness associated withnarcolepsy, sleep apnea (preferably obstructive sleep apnea/hypopnea)and shift work disorder), treatment of Parkinson's disease, Alzheimer'sdisease, cerebral ischemia, stroke, eating disorders, attention deficitdisorder (“ADD”), attention deficit hyperactivity disorder (“ADHD”),depression, schizophrenia, fatigue (preferably fatigue associated withcancer or neurological diseases, such as multiple sclerosis and chronicfatigue syndrome), stimulation of appetite and weight gain andimprovement of cognitive dysfunction.

These compounds have the structure:

and its stereoisomeric forms, mixtures of stereoisomeric forms, orpharmaceutically acceptable salt forms thereof, wherein the constituentmembers are defined infra.

In another aspect, the present invention is directed to a pharmaceuticalcomposition which comprises a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of the present invention.

In yet another aspect, the present invention is directed to methods ofpreventing or treating the diseases or disorders disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect of the present invention there are provided compounds offormula (A) for the utilities provided herein:

wherein

-   rings A and B, together with the carbon atoms to which they are    attached, are each independently selected from:    -   a) a 6-membered aromatic carbocyclic ring in which from 1 to 3        carbon atoms may be replaced by hetero atoms selected from        oxygen, nitrogen and sulfur; and    -   b) a 5-membered aromatic carbocyclic ring in which either:        -   i) one carbon atom may be replaced with an oxygen, nitrogen,            or sulfur atom;        -   ii) two carbon atoms may be replaced with a sulfur and a            nitrogen atom, an oxygen and a nitrogen atom, or two            nitrogen atoms; or        -   iii) three carbon atoms may be replaced with three nitrogen            atoms, one oxygen and two nitrogen atoms, or one sulfur and            two nitrogen atoms;    -   wherein said rings are optionally substituted with one to three        R²⁰ groups;-   X is not present, is a bond, O, S(O)_(y), NR¹⁰, C₂ alkylene, C₂₋₃    alkenylene, C(═O), C(R²¹)₂NR¹⁰, C(R²¹)═N, N═C(R²¹), C(═O)N(R¹⁰), or    NR¹⁰C(═O); wherein said alkylene and alkenylene groups are    optionally substituted with one to three R²⁰ groups;-   R is H, C₁-C₆ alkyl, C₆-C₁₀ aryl, 5-6 membered heteroaryl, C₃-C₇    cycloalkyl, or 3-7 membered heterocycloalkyl; with the proviso that    R cannot be H when R¹ is C(═O)NR¹²R¹³;-   Y is C₁-C₉ alkylene-R¹, wherein one or two carbon atoms can be    replaced by one or two O, NR¹⁰, or S(O)_(y) groups, or a carbon atom    can be replaced by a C₆-C₁₀ arylene, 5-10 membered heteroarylene,    C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene group;    C₂-C₆ alkenylene-R¹; or C₂-C₆ alkynylene-R¹; wherein said alkylene,    alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and    heterocycloalkylene groups are optionally substituted with one to    three R²⁰ groups;-   R¹ is selected from H, NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁵, CO₂R¹¹,    OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴, C(═NR¹¹)NR¹²R¹³,    NR²¹S(O)₂R¹¹, S(O)₂NR¹²R¹³, NR²¹S(O)₂NR¹²R¹³, and PO(OR²¹)₂;-   R¹⁰ and R^(10A) at each occurrence are independently selected from    H, C₁-C₆ alkyl, C₆-C₁₀ aryl, C(═O)R¹⁵, and S(O)_(y)R¹⁴; wherein said    alkyl and aryl groups are optionally substituted with one to three    R²⁰ groups;-   R¹¹ at each occurrence is independently selected from H, and C₁-C₆    alkyl; wherein said alkyl is optionally substituted with one to    three R²⁰ groups;-   R¹² and R¹³ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocycloalkyl ring;    -   wherein said alkyl and aryl groups and heterocycloalkyl ring are        optionally substituted with one to three R²⁰ groups;-   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, and arylalkyl; wherein said alkyl, aryl and arylalkyl    groups are optionally substituted with one to three R²⁰ groups;-   R¹⁵ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, arylalkyl, and heteroaryl; wherein said alkyl, aryl,    arylalkyl, and heteroaryl groups are optionally substituted with one    to three R²⁰ groups;-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²¹, OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆    spirocycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7    membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,    arylalkyl, ═O, C(═O)R²², CO₂R²¹, OC(═O)R²², C(═O)NR²³R²⁴,    NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹C(═S)R²²,    and S(O)_(y)R²²;-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;-   R²² at each occurrence is independently selected from C₁-C₆ alkyl,    and C₆-C₁₀ aryl;-   R²³ and R²⁴ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocycloalkyl ring;-   R²⁵ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;-   q is 0, 1, or 2;-   y is 0, 1, or 2;    with the proviso that when R=H and Y is (C₁-C₆    alkylene)-C(═O)NR¹²R¹³, then the alkylene group must be substituted    with a spirocycloalkyl group;    with the additional proviso that when Y is (C₁-C₄    alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n)-C(═O)NR¹²R¹³, then R must be    C₁-C₆ alkyl;    and the stereoisomeric forms, mixtures of stereoisomeric forms or    pharmaceutically acceptable salts forms thereof.

In an additional aspect of the present invention there are providedcompounds of formula (I):

wherein

-   rings A and B, together with the carbon atoms to which they are    attached, are each independently selected from:    -   a) a 6-membered aromatic carbocyclic ring in which from 1 to 3        carbon atoms may be replaced by hetero atoms selected from        oxygen, nitrogen and sulfur; and    -   b) a 5-membered aromatic carbocyclic ring in which either:        -   i) one carbon atom may be replaced with an oxygen, nitrogen,            or sulfur atom;        -   ii) two carbon atoms may be replaced with a sulfur and a            nitrogen atom, an oxygen and a nitrogen atom, or two            nitrogen atoms; or        -   iii) three carbon atoms may be replaced with three nitrogen            atoms, one oxygen and two nitrogen atoms, or one sulfur and            two nitrogen atoms;    -   wherein said rings are optionally substituted with one to three        R²⁰ groups;-   X is not present, is a bond, O, S(O)_(y), NR¹⁰, C₂ alkylene, C₂₋₃    alkenylene, C(═O), C(R²¹)₂NR¹⁰, C(R²¹)═N, N═C(R²¹), C(═O)N(R¹⁰), or    NR¹⁰C(═O); wherein said alkylene and alkenylene groups are    optionally substituted with one to three R²⁰ groups;-   R is H or C₁-C₆ alkyl;-   Y is selected from:    -   a) C₁-C₆ alkylene-R¹;    -   b) C₁-C₆ alkylene-R²;    -   c) (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n)-R¹;    -   d) C₁-C₆ alkylene-O(CH₂)_(p)OR²¹,    -   e) C₁-C₆ alkyl substituted with one or two OR²¹ groups; provided        that Y cannot be (CH₂)₁₋₄OR²¹; and    -   f) CH₂CR²¹═C(R²¹)₂ except when X is a bond and q is 2;    -   wherein said alkyl and alkylene groups are optionally        substituted with one to three R²⁰ groups;-   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C═C(R²¹)₂, C≡C, C₆-C₁₀    arylene, 5-10 membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6    membered heterocycloalkylene; wherein said arylene, heteroarylene,    cycloalkylene, and heterocycloalkylene groups are optionally    substituted with one to three R²⁰ groups;-   R¹ is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁵, CO₂R¹¹,    OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴, C(═NR¹¹)NR¹²R¹³,    NR²¹S(O)₂R¹¹, S(O)₂NR¹²R¹³, NR²¹S(O)₂NR¹²R¹³, and PO(OR²¹)₂;-   R² is a 5-6 membered heteroaryl, wherein said heteroaryl group is    optionally substituted with one to three R²⁰ groups;-   R¹⁰ and R^(10A) at each occurrence are independently selected from    H, C₁-C₆ alkyl, C₆-C₁₀ aryl, C(═O)R¹⁵, and S(O)_(y)R¹⁴; wherein said    alkyl and aryl groups are optionally substituted with one to three    R²⁰ groups;-   R¹¹ at each occurrence is independently selected from H and C₁-C₆    alkyl; wherein said alkyl is optionally substituted with one to    three R²⁰ groups;-   R¹² and R¹³ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocycloalkyl ring;    -   wherein said alkyl and aryl groups and heterocycloalkyl ring are        optionally substituted with one to three R²⁰ groups;-   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, and arylalkyl; wherein said alkyl, aryl and arylalkyl    groups are optionally substituted with one to three R²⁰ groups;-   R¹⁵ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, arylalkyl, and heteroaryl; wherein said alkyl, aryl,    arylalkyl, and heteroaryl groups are optionally substituted with one    to three R²⁰ groups;-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²¹, OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆    spirocycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7    membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,    arylalkyl, ═O, C(═O)R²², CO₂R²¹, OC(═O)R²², C(═O)NR²³R²⁴,    NR²C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹C(═S)R²²,    and S(O)_(y)R²²;-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;-   R²² at each occurrence is independently selected from C₁-C₆ alkyl,    and C₆-C₁₀ aryl;-   R²³ and R²⁴ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocycloalkyl ring;-   R²⁵ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;-   m is 0 or 1;-   n is 0 or 1;-   p is 1, 2, 3, or 4;-   q is 0, 1, or 2;-   y is 0, 1, or 2;    with the following provisos:    -   1) when Y is (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄        alkylene)_(n)-C(═O)NR¹²R¹³, then R must be C₁-C₆ alkyl;    -   2) Y cannot be    -    wherein J is C₂-C₄ alkylene or C₁-C₃ alkylene-CO—;    -   3) when R=H, Y is (C₁-C₆ alkylene)-R¹, and R¹ is CO₂R¹¹,        C(═O)NR¹²R¹³, or C(═NR¹¹)NR¹²R¹³, then the C₁-C₆ alkylene group        must be substituted with a spirocycloalkyl group;    -   4) when X is not present, then Y cannot be C₁-C₆ alkyl-NR¹²R¹³,        or —CH═CHCO₂R¹¹;    -   5) when X is a bond and Y is C₁-C₆ alkylene-NR¹²R¹³, then R¹²        and R¹³ are each independently selected from H, C₁-C₆ alkyl, and        C₆-C₁₀ aryl;        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof.

Other embodiments of compounds of formula (I), when X is not present, oris a bond, then Y cannot be C₁-C₆ alkylene-NR¹²R¹³. In another aspect,when X is not present, then R¹ cannot be NR¹²R¹³. In an additionalaspect, R¹ does not include C(═O)NR²¹OR¹⁴. In a further aspect, when Xis not present, R is H and Y is C₁-C₆ alkylene-C(═O)NR¹²R¹³, then R¹²and R¹³ do not include alkyl substituted with OR²¹ or NR²³R²⁴; and inother aspects R¹² and R¹³ do not include substituted alkyl.

In yet another embodiment of the present invention there are providedcompounds of formula (II):

wherein

-   rings A and B, together with the carbon atoms to which they are    attached, are each independently selected from phenylene,    pyridylene, thienylene, or a 5-membered aromatic ring in which one    or two carbon atoms may be replaced with a nitrogen atom;    -   wherein said rings are optionally substituted with one to three        R²⁰ groups;-   X is not present, is a bond, O, S(O)_(y), NR¹⁰, C₂ alkylene, or C₂    alkenylene, wherein said alkylene and alkenylene groups are    optionally substituted with one to three R²⁰ groups;-   R is H or C₁-C₆ alkyl;-   Y is selected from:    -   a) C₁-C₆ alkylene-R¹;    -   b) C₁-C₆ alkylene-R²;    -   c) (C₁-C₄ alkylene)_(m)-Z¹-(C₁-C₄ alkylene)_(n)—R¹, or C₁-C₄        alkylene-Z²-C₁-C₄ alkylene-R¹;    -   d) C₁-C₆ alkylene-O(CH₂)_(p)OR²¹,    -   e) C₁-C₆ alkyl substituted with one or two OR²¹ groups; provided        that Y cannot be (CH₂)₁₋₄OR²¹;    -   f) CH₂CR²¹═C(R²¹)₂ CH₂CR²¹═C(R²¹)₂ except when X is a bond and q        is 2;        -   wherein said alkyl and alkylene groups are optionally            substituted with one to three R²⁰ groups;-   Z¹ is CR²¹═CR²¹, C═C(R²¹)₂, C≡C, phenylene, 5-6 membered    heteroarylene, C₃-C₆ cycloalkylene, or 5-6 membered    heterocycloalkylene; wherein said phenylene, heteroarylene,    cycloalkylene, and heterocycloalkylene groups are optionally    substituted with one to three R²⁰ groups;-   Z² is O, NR^(10A), S(O)_(y);-   R¹ is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁵, CO₂R¹¹,    OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴, C(═NR¹¹)NR¹²R¹³,    NR²¹S(O)₂R¹¹, S(O)₂NR¹²R¹³, NR²¹S(O)₂NR¹²R¹³, and PO(OR²¹)₂;-   R² is a 5-6 membered heteroaryl, wherein said heteroaryl group is    optionally substituted with one to three R²⁰ groups;-   R¹⁰ and R^(10A) at each occurrence are independently selected from    H, C₁-C₆ alkyl, C₆-C₁₀ aryl, C(═O)R¹⁵, and S(O)_(y)R¹⁴; wherein said    alkyl and aryl groups are optionally substituted with one to three    R²⁰ groups;-   R¹¹ at each occurrence is independently selected from H, and C₁-C₆    alkyl; wherein said alkyl is optionally substituted with one to    three R²⁰ groups;-   R¹² and R¹³ at each occurrence are each independently selected from    H, C₁-C₆ allyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocycloalkyl ring;    -   wherein said alkyl and aryl groups and heterocycloalkyl ring are        optionally substituted with one to three R²⁰ groups;-   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, and arylalkyl; wherein said alkyl, aryl and arylalkyl    groups are optionally substituted with one to three R²⁰ groups;-   R¹⁵ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, arylalkyl, and heteroaryl; wherein said alkyl, aryl,    arylalkyl, and heteroaryl groups are optionally substituted with one    to three R²⁰ groups;-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²¹, OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆    spirocycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7    membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,    arylalkyl, ═O, C(═O)R²², CO₂R²¹, OC(═O)R²², C(═O)NR²³R²⁴,    NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹C(═S)R²²,    and S(O)_(y)R²²;-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;-   R²² at each occurrence is independently selected from C₁-C₆ alkyl,    and C₆-C₁₀ aryl;-   R²³ and R²⁴ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocycloalkyl ring;-   R²⁵ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;-   m is 0 or 1;-   n is 0 or 1;-   p is 1, 2, 3, or 4;-   q is 0, 1, or 2;-   y is 0, 1, or 2;    with the following provisos:    -   1) when Y is (C₁-C₄ alkylene)_(m)-Z¹-(C₁-C₄ alkylene),        —C(═O)NR¹²R¹³ or C₁-C₄ alkylene-Z²-C₁-C₄ alkylene-C(═O)NR¹²R¹³,        then R must be C₁-C₆ alkyl;    -   2) Y cannot be    -    wherein J is C₂-C₄ alkylene or C₁-C₃ alkylene-CO—;    -   3) when R=H, Y is (C₁-C₆ alkylene)-R¹, and R¹ is CO₂R¹¹,        C(═O)NR¹²R¹³, or C(═NR¹¹)NR¹²R¹³, then the C₁-C₆ alkylene group        must be substituted with a spirocycloalkyl group;    -   4) when X is not present, then Y cannot be C₁-C₆ alkyl-NR¹²R¹³,        or —CH═CHCO₂R¹¹;    -   5) when X is a bond and Y is C₁-C₆ alkylene-NR¹²R¹³, then R¹²        and R¹³ are each independently selected from H, C₁-C₆ alkyl, and        C₆-C₁₀ aryl;        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof.

Other embodiments of compounds of formula (II), when X is not present,or is a bond, then Y cannot be C₁-C₆ alkylene-NR¹²R¹³. In anotheraspect, when X is not present, then R¹ cannot be NR¹²R¹³. In anadditional aspect, R¹ does not include C(═O)NR²¹OR¹⁴. In a furtheraspect, when X is not present, R is H and Y is C₁-C₆alkylene-C(═O)NR¹²R¹³, then R¹² and R¹³ do not include alkyl substitutedwith OR²¹ or NR²³R²⁴; and in other aspects R¹² and R¹³ do not includesubstituted alkyl.

In yet another embodiment of the present invention there are providedcompounds of formula (III):

wherein

-   rings A and B, together with the carbon atoms to which they are    attached, are each independently selected from phenylene,    pyridylene, furylene, thienylene, or a 5-membered aromatic ring in    which 1-3 carbon atoms may be replaced with a nitrogen atom;    -   wherein said rings are optionally substituted with one to three        R²⁰ groups;-   X is not present, is a bond, O, S(O)_(y), or NR¹⁰, wherein said    alkylene and alkenylene groups are optionally substituted with one    to three R²⁰ groups;-   R is H or C₁-C₄ alkyl;-   Y is selected from:    -   a) C₁-C₆ alkylene-R¹;    -   b) C₁-C₆ alkylene-R²;    -   c) (C₁-C₄ alkylene)_(m)-Z¹-(C₁-C₄ alkylene)_(n)—R¹, or C₁-C₄        alkylene-Z²-C₁-C₄ alkylene-R¹;    -   d) C₁-C₆ alkylene-O(CH₂)_(p)OR²¹,    -   e) CH₂C(OH)(CH₃)₂, CH₂C(CH₃)₂OH, CH₂C(OH)₂CF₃, CH₂C(OH)(C═CH)₂,        or CH₂CH(OH)CH₃, and    -   f) CH₂CR²¹═C(R²¹)₂, or CH₂CR²¹═C(R²¹)₂ except when X is a bond        and q is 2;        -   wherein said alkyl and alkylene groups are optionally            substituted with one to three R²⁰ groups;-   Z¹ is CR²¹═CR²¹, C═C(R²¹)₂, C≡C, or phenylene; wherein said    phenylene group is optionally substituted with one to three R²⁰    groups;-   Z² is O, NR^(10A) or S(O)_(y);-   R¹ is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁵, CO₂R¹¹,    C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴, NR²¹S(O)₂R¹¹, S(O)₂NR¹²R¹³, and    PO(OR²¹)₂;-   R² is pyridyl, furyl, thienyl, or a 5-membered heteroaryl group    containing 1-3 nitrogen atoms; wherein said heteroaryl group is    optionally substituted with one to three R²⁰ groups;-   R¹⁰ and R^(10A) at each occurrence are independently selected from    H, C₁-C₆ alkyl, C₆-C₁₀ aryl, C(═O)R¹⁵, and S(O)_(y)R¹⁴; wherein said    alkyl and aryl groups are optionally substituted with one to three    R²⁰ groups;-   R¹¹ at each occurrence is independently selected from H, and C₁-C₆    alkyl; wherein said alkyl is optionally substituted with one to    three R²⁰ groups;-   R¹² and R¹³ at each occurrence are each independently selected from    H and C₁-C₆ alkyl or R¹² and R¹³, together with the nitrogen to    which they are attached, form a 5-6 membered heterocycloalkyl;    -   wherein said alkyl and heterocycloalkyl groups are optionally        substituted with one to three R²⁰ groups;-   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, and arylalkyl;    -   wherein said alkyl, aryl and arylalkyl groups are optionally        substituted with one to three R²⁰ groups;-   R¹⁵ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, arylalkyl, and heteroaryl; wherein said alkyl, aryl,    arylalkyl, and heteroaryl groups are optionally substituted with one    to three R²⁰ groups;-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²¹, OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆    spirocycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7    membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,    arylalkyl, ═O, C(═O)R²², CO₂R²¹, OC(═O)R²², C(═O)NR²³R²⁴,    NR²C(═O)R²², N²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²C(═S)R²²,    and S(O)_(y)R²²;-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;-   R²² at each occurrence is independently selected from C₁-C₆ alkyl,    and phenyl;-   R²³ and R²⁴ at each occurrence are each independently selected from    H and C₁-C₆ alkyl, or R²³ and R²⁴, together with the nitrogen to    which they are attached, form a 5-6 membered heterocycloalkyl;-   R²⁵ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;-   m is 0 or 1;-   n is 0 or 1;-   p is 1, 2, 3, or 4;-   q is 0, 1, or 2;-   y is 0, 1, or 2;    with the following provisos:    -   1) when Y is (C₁-C₄ alkylene)_(m)-Z¹-(C₁-C₄        alkylene)_(n)-C(═O)NR¹²R¹³ or C₁-C₄ alkylene-Z²-C₁-C₄        alkylene-C(═O)NR¹²R¹³, then R must be C₁-C₆ alkyl;    -   2) when R=H, Y is (C₁-C₆ alkylene)-R¹, and R¹ is CO₂R¹¹ or        C(═O)NR¹²R¹³, then the C₁-C₆ alkylene group must be substituted        with a spirocycloalkyl group;    -   3) when X is not present, then Y cannot be C₁-C₆ alkyl-NR¹²R¹³,        or —CH═CHCO₂R¹¹;    -   4) when X is a bond and Y is C₁-C₆ alkylene-NR¹²R¹³, then R¹²        and R¹³ are each independently selected from H or C₁-C₆ alkyl;        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof.

Other embodiments of compounds of formula (III), when X is not present,or is a bond, then Y cannot be C₁-C₆ alkylene-NR¹²R¹³. In anotheraspect, when X is not present, then R¹ cannot be NR¹²R¹³. In anadditional aspect, R¹ does not include C(═O)NR²¹OR¹⁴. In a furtheraspect, when X is not present, R is H and Y is C₁-C₆alkylene-C(═O)NR¹²R¹³, then R¹² and R¹³ do not include alkyl substitutedwith OR²¹ or NR²³R²⁴; and in other aspects R¹² and R¹³ do not includesubstituted alkyl.

In a further embodiment of the present invention there are providedcompounds of formula (IV):

wherein

-   the phenylene rings are each independently optionally substituted    with one to three R²⁰ groups;-   X is not present or is a bond;-   R is H or C₁-C₄ alkyl;-   Y is selected from:    -   a) C₁-C₆alkylene-R¹;    -   b) C₁-C₆ alkylene-R²;    -   c) C₁-C₄ alkylene-O(CH₂)_(p)OR²¹,    -   d) CH₂C(OH)(CH₃)₂, CH₂C(CH₃)₂OH, CH₂C(OH)₂CF₃, CH₂C(OH)(C≡CH)₂,        or CH₂CH(OH)CH₃, and    -   e) CH₂CR²¹═C(R²¹)₂ CH₂CR²¹═C(R²¹)₂ except when X is a bond and q        is 2;    -   wherein said alkylene groups optionally substituted with an R²⁰        group;-   R¹ is selected from pyrrolidinyl, piperidinyl, morpholinyl,    NR²C(═O)R¹⁴, C(═O)R¹⁵, CO₂R¹¹, C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴,    NR²¹S(O)₂R¹¹, S(O)₂NR²¹R^(13A), and PO(OR²¹)₂;-   R² is furyl, thienyl, a 5-membered heteroaryl group containing 1-2    nitrogen atoms, or triazolyl; wherein said R² groups are optionally    substituted with an R²⁰ group;-   R¹¹ at each occurrence is independently C₁-C₆ alkyl;-   R¹² and R¹³ at each occurrence are each independently selected from    H and C₁-C₆ alkyl, or R¹² and R¹³, together with the nitrogen to    which they are attached, form a 5-6 membered heterocycloalkyl;    -   wherein said alkyl and heterocycloalkyl groups are optionally        substituted with an R²⁰ group;-   R¹² and R^(13A) at each occurrence are each independently selected    from H and C₁-C₆ alkyl;-   R¹⁴ at each occurrence is independently C₁-C₆ alkyl;-   R¹⁵ at each occurrence is independently selected from C₁-C₆ alkyl,    and 5-membered heteroaryl;-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²¹, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆    spirocycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7    membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,    arylalkyl, ═O, C(═O)R²², CO₂R²¹, OC(═O)R²², C(═O)NR²³R²⁴,    NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹C(═S)R²²,    and S(O)_(y)R²²;-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;-   R²² at each occurrence is independently selected from C₁-C₆ alkyl,    and phenyl;-   R²³ and R²⁴ at each occurrence are each independently selected from    H and C₁-C₆ alkyl, or R²³ and R²⁴, together with the nitrogen to    which they are attached, form a 5-6 membered heterocycloalkyl;-   R²⁵ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;-   p is 1, 2, 3, or 4;-   q is 1 or 2;-   y is 0, 1, or 2;    with the following provisos:    -   1) when R=H, Y is (C₁-C₆ alkylene)-R¹, and R¹ is CO₂R¹¹ or        C(═O)NR¹²R¹³, then the C₁-C₆ alkylene group must be substituted        with a spirocycloalkyl group;    -   2) when X is not present, then Y cannot be C₁-C₆ alkyl-NR¹²R¹³,        wherein NR¹²R¹³ is pyrrolidinyl, piperidinyl, or morpholinyl;        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof.

Other embodiments of compounds of formula (IV), when X is not present,or is a bond, then Y cannot be C₁-C₆ alkyl-NR¹²R¹³, wherein NR¹²R¹³ ispyrrolidinyl, piperidinyl, or morpholinyl. In another aspect, when X isnot present, then R¹ cannot be pyrrolidinyl, piperidinyl, morpholinyl,or C(═O)NR²¹OR¹⁴. In a further aspect, when X is not present, R is H andY is C₁-C₆ alkylene-C(═O)NR¹²R¹³, then R¹² and R¹³ do not include alkylsubstituted with OR²¹ or NR²³R²⁴; and in other aspects R¹² and R¹³ donot include substituted alkyl.

A further aspect of the present invention includes compounds of formula(IV) wherein Y is selected from:

-   -   a) C₁-C₄ alkylene-R¹;    -   b) C₁-C₄ alkylene-R²;    -   c) C₁-C₄ alkylene-O(CH₂)_(p)OR²¹,    -   d) CH₂C(OH)(CH₃)₂, CH₂C(CH₃)₂OH, CH₂C(OH)₂CF₃, CH₂C(OH)(C CH)₂,        or CH₂CH(OH)CH₃,    -   e) CH₂CH═CH₂, or CH₂C(═C)CH₃ except when X is a bond and q is 2;    -   wherein said alkylene groups are optionally substituted with an        R²⁰ group;

-   R¹ is selected from pyrrolidinyl, piperidinyl, morpholinyl,    NR²¹C(═O)R¹⁴, C(═O)R¹⁵, CO₂R¹¹, C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴,    NR²¹S(O)₂R¹¹, S(O)₂NR^(12A)R^(13A), and PO(OR²¹)₂;

-   R² is furyl, thienyl, or triazolonyl; wherein said R² groups are    optionally substituted with an R²⁰ group;

-   R¹¹ at each occurrence is independently C₁-C₄ alkyl;

-   R¹² and R¹³ at each occurrence are each independently selected from    H and C₁-C₄ alkyl, optionally substituted with C(═O)NR^(12A)R^(13A),    or R¹² and R¹³, together with the nitrogen to which they are    attached, form a pyrrolidinyl or piperidinyl ring;

-   R^(12A) and R^(13A) at each occurrence are each independently    selected from H and C₁-C₄ alkyl;

-   R¹⁴ at each occurrence is independently C₁-C₄ alkyl;

-   R¹⁵ at each occurrence is independently selected from C₁-C₄ alkyl,    and thienyl;

-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²¹, OR², NR²³R²⁴, NHOH, NO₂, CN, CF₃, ═O, C(═O)R²², CO₂R²¹,    C(═O)NR²³R²⁴, or NR²¹C(═O)R¹²;

-   R²¹ at each occurrence is independently selected from H and C₁-C₄    alkyl;

-   R²² at each occurrence is independently C I—C₄ alkyl;

-   R²³ and R²⁴ at each occurrence are each independently selected from    H and C₁-C₄ alkyl, or R²³ and R²⁴, together with the nitrogen to    which they are attached, form a 5-6 membered heterocycloalkyl;

-   R²⁵ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;

-   p is 1, 2, 3, or 4;

-   q is 0, 1, or 2.

In a further embodiment of the present invention there are providedcompounds of formula (V):

wherein

-   the phenylene rings are each independently optionally substituted    with one to three R²⁰ groups;-   X is a bond, O, S(O)_(y), NR¹⁰, C₂ alkylene, or C₂ alkenylene,    wherein said alkylene and alkenylene groups are optionally    substituted with an R²⁰ group;-   R is H or C₁-C₄ alkyl;-   Y is selected from:    -   a) C₁-C₆ alkylene-R¹;    -   b) CH₂CR²¹═C(R²¹)₂ CH₂CR²¹═C(R²¹)₂ except when X is a bond and q        is 2;-   R¹ is selected from pyrrolidinyl, piperidinyl, morpholinyl,    NR²¹C(═O)R¹⁴, C(═O)NR¹² R¹³, and NR²¹S(O)₂R¹¹;-   R¹⁰ is independently selected from H, C₁-C₆ alkyl, C₆-C₁₀ aryl,    C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl groups are    optionally substituted with one to three R²⁰ groups;-   R¹¹ at each occurrence is independently C₁-C₆ alkyl;-   R¹² and R¹³ at each occurrence are each independently selected from    H and C₁-C₆ alkyl, or R¹² and R¹³, together with the nitrogen to    which they are attached, form a 5-6 membered heterocycloalkyl;    -   wherein said alkyl and heterocycloalkyl groups are optionally        substituted with an R²⁰ group;-   R¹⁴ at each occurrence is independently C₁-C₆ alkyl;-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²¹, OR²¹, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆    spirocycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7    membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,    arylalkyl, ═O, C(═O)R²², CO₂R²¹, OC(═O)R²², C(═O)NR²³R²⁴,    NR²¹C(═O)R²², NR²¹CO R²², OC(═O)NR²³R²⁴, NR²¹OC(═O)R²²,    NR²¹C(═S)R²², and S(O)_(y)R;-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;-   R²² at each occurrence is independently selected from C₁-C₆ alkyl,    and phenyl;-   R²³ and R²⁴ at each occurrence are each independently selected from    H and C₁-C₆ alkyl, or R²³ and R²⁴, together with the nitrogen to    which they are attached, form a 5-6 membered heterocycloalkyl;-   R²⁵ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;-   y is 0, 1, or 2;    with the proviso that when R=H, Y is (C₁-C₆ alkylene)-C(═O)NR¹²R¹³,    then the C₁-C₆ alkylene group must be substituted with a    spirocycloalkyl group;    and the stereoisomeric forms, mixtures of stereoisomeric forms or    pharmaceutically acceptable salts forms thereof.

A further aspect of the present invention includes compounds of formula(V) wherein X is a bond; R is C₁-C₄ alkyl, Y is C₁-C₆alkyl-C(═O)NR¹²R¹³.

Another aspect includes compounds of formula (V) wherein X is a bond; Ris H, Y is C₁-C₆ alkyl-R¹, and R¹ is selected from pyrrolidinyl,piperidinyl, morpholinyl, NR²¹C(═O)R¹⁴, or NR²¹S(O)₂R¹¹.

A further aspect includes compounds of formula (V) wherein X is a bondand Y is CH₂CR²¹═C(R²¹)₂ CH₂CR²¹═C(R²¹)₂.

In yet another aspect, there are included compounds of formula (V)wherein Y is CH₂CH═CH₂, or CH₂C(═C)CH₃.

An additional aspect includes compounds of formula (V) wherein thephenylene rings are each independently optionally substituted with oneto three R²⁰ groups;

-   q is 1;-   X is a bond;-   Y is selected from:    -   a) C₁-C₄ alkylene-R¹;    -   b) CH₂CH═CH₂, or CH₂C(═C)CH₃ except when X is a bond and q is 2;-   R¹ is selected from pyrrolidinyl, piperidinyl, morpholinyl,    NR²¹C(═O)R¹⁴, C(═O)NR¹²R¹³, and NR²¹S(O)₂R¹¹;-   R¹¹ at each occurrence is independently C₁-C₄ alkyl;-   R¹² and R¹³ at each occurrence are each independently selected from    H and C₁-C₄ alkyl, optionally substituted with C(═O)NR^(12A)R^(13A),    or R¹² and R¹³, together with the nitrogen to which they are    attached, form a pyrrolidinyl or piperidinyl ring;-   R^(12A) and R^(13A) at each occurrence are each independently    selected from H and C₁-C₄ alkyl;-   R¹⁴ at each occurrence is independently C₁-C₄ alkyl;-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²¹, OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, ═O, C(═O)R²², CO₂R²¹,    C(═O)NR²³R²⁴, or NR²¹C(═O)R²²;-   R²¹ at each occurrence is independently selected from H and C₁-C₄    alkyl;-   R²² at each occurrence is independently C₁-C₄ alkyl;-   R²³ and R²⁴ at each occurrence are each independently selected from    H and C₁-C₄ alkyl, or R²³ and R²⁴, together with the nitrogen to    which they are attached, form a 5-6 membered heterocycloalkyl;-   R²⁵ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed.

In yet another embodiment of the present invention there are providedcompounds of formula (VI):

wherein

-   Ar¹ and Ar² are each independently phenyl optionally substituted    with one to three R²⁰ groups;-   R is H or C₁-C₄ alkyl;-   Y is selected from:    -   a) C₁-C₆ alkylene-R¹;    -   b) C₁-C₆ alkylene-R²;    -   c) C₁-C₆ alkylene-O(CH₂)_(p)OR²¹,    -   d) CH₂C(OH)(CH₃)₂, CH₂C(CH₃)₂OH, CH₂C(OH)₂CF₃, CH₂C(OH)(C CH)₂,        or CH₂CH(OH)CH₃;-   R¹ is selected from C(═O)R¹⁵, CO₂R¹¹, C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴,    S(O)₂NR^(12A)R^(13A), and PO(OR²¹)₂;-   R² is furyl, thienyl, or triazolyl; wherein said R² groups are    optionally substituted with an R²⁰ group;-   R¹¹ at each occurrence is independently C₁-C₆ alkyl;-   R¹² and R¹³ at each occurrence are each independently selected from    H and C₁-C₆ alkyl, or R¹² and R¹³, together with the nitrogen to    which they are attached, form a 5-6 membered heterocycloalkyl;-   R^(12A) and R^(13A) at each occurrence are each independently    selected from H and C₁-C₆ alkyl;-   R¹⁴ at each occurrence is independently C₁-C₆ alkyl;-   R¹⁵ at each occurrence is independently selected from C₁-C₆ alkyl,    and 5-membered heteroaryl;-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²¹, OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆    spirocycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7    membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,    arylalkyl ═O, C(═O)R²², C₂R²¹, OC(═O)R²², C(═O)NR²³R²⁴,    NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹C(═S)R²²,    and S(O)_(y)R²²;-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;-   R²² at each occurrence is independently selected from C₁-C₆ alkyl    and phenyl;-   R²³ and R²⁴ at each occurrence are each independently selected from    H and C₁-C₆ alkyl, or R²³ and R²⁴, together with the nitrogen to    which they are attached, form a 5-6 membered heterocycloalkyl;-   R²⁵ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;-   p is 1, 2, 3, or 4;-   y is 0, 1, or 2;    with the proviso that when R=H, Y is (C₁-C₆ alkylene)-R¹, and R¹ is    CO₂R¹¹ or C(═O)NR¹²R¹³, then the C₁-C₆ alkylene group must be    substituted with a spirocycloalkyl group;    and the stereoisomeric forms, mixtures of stereoisomeric forms or    pharmaceutically acceptable salts forms thereof.

A further aspect of the present invention includes compounds of formula(VI) wherein R is C₁-C₄ alkyl, and Y is C₁-C₆alkyl-C(═O)NR¹²R¹³. Inanother aspect, R¹ is C(═O)R¹⁵, CO₂R¹¹, C(═O)NR¹²R¹³,S(O)₂NR^(12A)R^(13A), or PO(OR²¹)₂.

Another aspect includes compounds of formula (VI) wherein R is H, and Yis C₁-C₆ alkyl-R¹, wherein said alkyl is substituted withspirocycloalkyl, and R¹ is CO₂R¹¹, or C(═O)NR¹²R¹³.

A further aspect includes compounds of formula (VI) wherein R¹ isC(═O)NR¹²R¹³.

In yet another aspect, there are included compounds of formula (VI)wherein R¹ is selected from C(═O)R¹⁵, C(═O)NR²¹OR¹⁴,S(O)₂NR^(12A)R^(13A), and PO(OR²¹)₂.

An additional aspect includes compounds of formula (VI) wherein Y isC₁-C₆ alkylene-O(CH₂)_(p)OR²¹.

In a further aspect, there are compounds of formula (VI) wherein Y isCH₂C(OH)(CH₃)₂, CH₂C(CH₃)₂OH, CH₂C(OH)₂CF₃, CH₂C(OH)(C CH)₂, orCH₂CH(OH)CH₃.

In an additional aspect, there are compounds of formula (VI) wherein Ar¹and Ar² are each independently phenyl optionally substituted with one tothree R²⁰ groups;

-   R is H or C₁-C₄ alkyl;-   Y is selected from:    -   a) C₁-C₄ alkylene-R¹;    -   b) C₁-C₄ alkylene-R²;    -   c) CH₂CH₂O(CH₂)₂OCH₃,    -   d) CH₂C(OH)(CH₃)₂, CH₂C(CH₃)₂OH, CH₂C(OH)₂CF₃, CH₂C(OH)(C CH)₂,        or CH₂CH(OH)CH₃,-   R¹ is selected from C(═O)R¹⁵, CO₂R¹¹, C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴,    S(O)₂NR^(12A)R^(13A), and PO(OR²¹)₂;-   R² is furyl, thienyl, or triazolonyl;-   R¹¹ at each occurrence is independently C₁-C₄ alkyl;-   R¹² and R¹³ at each occurrence are each independently selected from    H and C₁-C₄ alkyl;-   R^(12A) and R^(13A) at each occurrence are each independently    selected from H and C₁-C₄ alkyl;-   R¹⁴ at each occurrence is independently C₁-C₄ alkyl;-   R¹⁵ at each occurrence is independently selected from C₁-C₄ alkyl,    and thienyl;-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²¹, OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₃-C₆ spirocycloalkyl, ═O,    C(═O)R²², CO₂R²¹, C(═O)NR²³R²⁴, and NR²¹C(═O)R²²;-   R²¹ at each occurrence is independently selected from H and C₁-C₄    alkyl;-   R²² at each occurrence is independently C₁-C₄ alkyl;-   R²³ and R²⁴ at each occurrence are each independently selected from    H and C₁-C₄ alkyl, or R²³ and R²⁴, together with the nitrogen to    which they are attached, form a 5-6 membered heterocycloalkyl;-   R²⁵ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;    with the following proviso:    -   1) when R=H, Y is (C₁-C₄ alkylene)-R¹, and R¹ is CO₂R¹¹ or        C(═O)NR¹²R¹³, then the alkylene group must be substituted with a        spirocycloalkyl group.

In still more aspects, there are compounds of formula (VI) wherein R isH; or R¹ selected from C(═O)R¹⁵, CO₂R¹¹, C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴,S(O)₂NR^(12A)R^(13A), and PO(OR²¹)₂; or Y is C₁-C₄alkylene-R¹.

In additional aspects of the present invention there are includedcompounds of any of the preceding formulas wherein q is 1 or 2. Incertain aspects, q is 0. In other aspects q is 1. In further aspects, qis 2.

In other aspects of the present invention, there are included compoundsof any of the preceding formulas wherein q can be any moieties of theprevious embodiments, and R can be selected as follows. In one aspect, Ris H. In other aspects, R is C₁-C₆ alkyl. In additional aspects, R isC₁-C₄ alkyl, preferably methyl or ethyl, and more preferably methyl.

In certain aspects of the present invention, there are includedcompounds of any of the preceding formulas wherein q and R can be anymoieties of the previous embodiments, and rings A and B can be selectedas follows. In one aspect, rings A and B are phenylene. In otheraspects, rings A and B are each independently selected from: a) a6-membered aromatic carbocyclic ring in which from 1 to 3 carbon atomsmay be replaced by nitrogen atoms, preferably pyridylene, pyrazinylene,or pyrimidinylene; and b) a 5-membered aromatic carbocyclic ring inwhich either: i) one carbon atom may be replaced with an oxygen,nitrogen, or sulfur atom; ii) two carbon atoms may be replaced with asulfur and a nitrogen atom, an oxygen and a nitrogen atom, or twonitrogen atoms; or iii) three carbon atoms may be replaced with threenitrogen atoms, one oxygen and two nitrogen atoms, or one sulfur and twonitrogen atoms. In an additional aspect, rings A and B are eachindependently selected from phenylene, pyridylene, thienylene, or a5-membered aromatic ring in which one or two carbon atoms may bereplaced with a nitrogen atom. In a further aspect, rings A and B areeach independently selected from phenylene, pyridylene, pyrazinylene,pyrimidinylene, pyrrolylene, pyrazolylene, imidazolylene, furylene, andthienylene.

In another aspect of the present invention, there are included compoundsof any of the preceding formulas wherein q, R, and rings A and B can beany moieties of the previous embodiments, and X can be selected asfollows. In one aspect, X is not present, is a bond, O, C₂ alkylene, orC(═O). In a further aspect, X is not present or is a bond. In anotheraspect, X is not present, and preferably the A-B—X moiety is Ph₂CH. Inan additional aspect, X is a bond, and preferably the tricyclic A-B—Xmoiety is fluorenyl. In another aspect, X is O, S(O)_(y), NR¹⁰, andpreferably O. Another aspect includes X as C₂ alkylene. In a furtheraspect, X is C₂₋₃ alkenylene, C(═O), C²¹)₂NR¹⁰, C(R²¹)═N, N═C(W²¹),C(═O)N(R¹⁰), or NR¹⁰C(═O).

In certain aspects of the present invention, there are includedcompounds of any of the preceding formulas wherein q, R, rings A and B,X and Y can be any moieties of the previous embodiments, and Y is C₁-C₆alkylene-R1, particularly those where Y is C₁-C₄ alkylene-R1, or Y isCH₂—R1 or Y is CH₂CH₂—R¹.

Other aspects of the present invention include compounds of any of thepreceding formulas wherein q, R, rings A and B, and X can be anymoieties of the previous embodiments, and Y can be selected as follows.One aspect is where Y is C₁-C₆ alkylene-R², particularly those where R²is furyl, thienyl or triazinyl, or 2-triazolonyl. In another aspect, Yis C₁-C₆ alkylene-O(CH₂)_(p)OR²¹, particularly those where Y isCH₂CH₂O(CH₂)₂OCH₃. In a further aspect, Y is C₁-C₆ alkyl substitutedwith one or two OR²¹ groups, wherein said alkyl group is furtheroptionally substituted with 1-3 R²⁰ groups, and in particular Y isCH₂C(OH)(CH₃)₂, or CH₂C(CH₃)₂OH, or CH₂C(OH)₂CF₃, or CH₂C(OH)(C CH)₂, orCH₂CH(OH)CH₃. In an additional aspect, Y is CH₂CR²¹═C(R²¹)₂, and inparticular Y is CH₂CH═CH₂, or CH₂C(═C)CH₃.

Additional aspects of the present invention include compounds of any ofthe preceding formulas wherein q, R, rings A and B, X and Y can be anymoieties of the previous embodiments, and Y is (C₁-C₄alkylene)_(m)-Z¹-(C₁-C₄ alkylene)_(n)-R¹, particularly those where Y isC₁-C₄ alkylene-Z¹-R¹, or Y is Z¹-C₁-C₄ alkylene-R¹, or Y is C₁-C₄alkylene-Z¹-C₁-C₄ alkylene-R¹.

Further aspects of the present invention include compounds of any of thepreceding formulas wherein q, R, rings A and B, X, and Y can be anymoieties of the previous embodiments, and Z¹ can be selected as follows.In one aspect, Z¹ is CR²¹═CR²¹, C═C(R²¹), C≡C, or phenylene, or moreparticularly where Z¹ is CR²¹═CR²¹ or Z¹ is phenylene. Other aspectsinclude compounds where Z¹ is CR²¹═CR²¹, or C≡C. Other aspects includecompounds where Z¹ is C₃-C₆ cycloalkylene, and in particular,cyclopentylene or cyclohexylene. Other aspects include compounds whereZ¹ is 5-10 membered heteroarylene, in particular 5-6 memberedheteroarylenes containing nitrogen, preferably containing 1 or 2nitrogen atoms. Additional aspects include compounds where Z¹ is 3-6membered heterocycloalkylene.

Further aspects of the present invention include compounds of any of thepreceding formulas wherein q, R, rings A and B, X and Y can be anymoieties of the previous embodiments, and Y is C₁-C₄ alkylene-Z²-C₁-C₄alkylene or Y is C₁-C₄ alkylene-Z², wherein Z² is O, NR^(10A), orS(O)_(y), particularly those where Z² is O. Additional aspects includeany of the above embodiments of Y wherein Z² is NR^(10A).

Further aspects of the present invention include compounds of any of thepreceding formulas wherein q, R, rings A and B, X, Y, Z¹, and Z² can beany moieties of the previous embodiments, and R¹ can be any moietyselected from the following enumerated paragraphs:

-   -   1. NR¹²R¹³, particularly those wherein R¹² and R¹³ at each        occurrence are each independently selected from H and C₁-C₆        alkyl, or those where R¹² and R¹³, together with the nitrogen to        which they are attached, form a 5-6 membered heterocycloalkyl,        particularly pyrrolidinyl, piperidinyl, or morpholinyl.    -   2. NR²¹C(═O)R¹⁴.    -   3. C(═O)R¹⁵, particularly those where R¹⁵ is C₁-C₄ alkyl, or        thienyl.    -   4. CO₂R¹¹, particularly those where R¹¹ is C₁-C₄ alkyl.    -   5. OC(═O)R¹¹.    -   6. C(═O)NR¹²R¹³.    -   7. C(═O)NR²¹OR¹⁴.    -   8. C(═NR¹¹)NR¹²R¹³.    -   9. NR²¹S(O)₂R¹³.    -   10. S(O)₂NR¹²R¹³.    -   11. NR²¹S(O)₂NR¹²R¹³.    -   12. PO(OR²¹)₂.

Other additional aspects of the present invention include compounds ofany of the preceding formulas wherein q, R, rings A and B, X, Y, Z¹, andZ² can be any moieties of the previous embodiments, and R¹ can be acombination of the values selected from the previous enumeratedparagraphs. The preceding enumerated paragraphs may be combined tofurther define additional preferred embodiments of compounds of any ofthe preceding formulas. For example, one such combination includesNR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁵, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³,C(═NR¹²R¹³)N²¹R¹³, NR²¹S(O)₂R¹¹, S(O)₂NR¹²R¹³, NR²¹S(O)₂NR¹²R¹³, orPO(OR²¹)₂. An additional combination includes NR¹²R¹³, NR²¹C(═O)R¹⁴,C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, NR²¹S(O)₂R¹¹, S(O)₂NR¹²R¹³,NR²¹S(O)₂NR¹²R¹³, or PO(OR²¹)₂.

A third such combination includes NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁵,C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴, NR²¹S(O)₂R¹¹, S(O)₂NR¹²R¹³, and PO(OR²¹)₂.

A fourth such combination includes NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)NR¹²R¹³,NR²¹S(O)₂R¹¹, or S(O)₂NR¹²R¹³.

A fifth such combination includes NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁵,C(═O)NR²¹OR¹⁴, NR²¹S(O)₂R¹¹, S(O)₂NR¹²R¹³, and PO(OR²¹)₂.

A sixth such combination includes C(═O)R¹⁵, C(═O)NR²¹OR¹⁴,S(O)₂NR^(12A)R^(13A), and PO(OR²¹)₂.

A seventh such combination includes C(═O)R¹⁵, C(═O)NR¹²R¹³,C(═O)NR²¹OR¹⁴, S(O)₂NR^(12A)R^(13A), and PO(OR²¹)₂.

An eighth such combination includes NR²¹C(═O)R¹⁴, C(═O)NR¹²R¹³,NR²¹S(O)₂R¹¹, and S(O)₂NR¹²R¹³.

Further aspects of the present invention include compounds of any of thepreceding formulas wherein q, R, rings A and B, X, Y, Z¹, Z², and R¹ canbe any moieties of the previous embodiments, and R¹² and R¹³ areindependently H or C₁-C₆ alkyl, or where R¹² and R¹³, together with thenitrogen to which they are attached, form a 3-7 memberedheterocycloalkyl ring. In another aspects, R¹² and R¹³, together withthe nitrogen to which they are attached, form a 5-6 memberedheterocycloalkyl ring containing from 1 to 2 nitrogen atoms, or morepreferably form pyrrolidinyl, piperidinyl, or morpholinyl. In certainaspects the heterocycloalkyl rings can be substituted with one R²⁰group, and in other aspects, the heterocycloalkyl rings areunsubstituted.

The following terms and expressions contained herein are defined asfollows:

As used herein, the term “about” refers to a range of values from ±10%of a specified value. For example, the phrase “about 50 mg” includes±10% of 50, or from 45 to 55 mg.

As used herein, a range of values in the form “x-y” or “x to y”, or “xthrough y”, include integers x, y, and the integers therebetween. Forexample, the phrases “1-6”, or “1 to 6” or “1 through 6” are intended toinclude the integers 1, 2, 3, 4, 5, and 6. Preferred embodiments includeeach individual integer in the range, as well as any subcombination ofintegers. For example, preferred integers for “1-6” can include 1, 2, 3,4, 5, 6, 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 2-6, etc.

As used herein “stable compound” or “stable structure” refers to acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and preferably capable offormulation into an efficacious therapeutic agent. The present inventionis directed only to stable compounds.

As used herein, the term “alkyl” refers to a straight-chain, or branchedalkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,neopentyl, 1-ethylpropyl, 3-methylpentyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, hexyl, octyl, etc. The alkyl moiety ofalkyl-containing groups, such as alkoxy, alkoxycarbonyl, andalkylaminocarbonyl groups, has the same meaning as alkyl defined above.Lower alkyl groups, which are preferred, are alkyl groups as definedabove which contain 1 to 4 carbons. A designation such as “C₁-C₄ alkyl”refers to an alkyl radical containing from 1 to 4 carbon atoms.

As used herein, the term “alkenyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon-carbon double bond. A designation “C₂-C₈ alkenyl” refers to analkenyl radical containing from 2 to 8 carbon atoms. Examples of alkenylgroups include ethenyl, propenyl, isopropenyl, 2,4-pentadienyl, etc.

As used herein, the term “alkynyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon-carbon triple bond. A designation “C₂-C₈ alkynyl” refers to analkynyl radical containing from 2 to 8 carbon atoms. Examples includeethynyl, propynyl, isopropynyl, 3,5-hexadiynyl, etc.

As used herein, the term “alkylene” refers to a substituted orunsubstituted, branched or straight chained hydrocarbon of 1 to 8 carbonatoms, which is formed by the removal of two hydrogen atoms. Adesignation such as “C₁-C₄ alkylene” refers to an alkylene radicalcontaining from 1 to 4 carbon atoms. Examples include methylene (—CH₂—),propylidene (CH₃CH₂CH═), 1,2-ethandiyl (—CH₂CH₂—), etc.

As used herein, the term “phenylene” refers to a phenyl group with anadditional hydrogen atom removed, i.e. a moiety with the structure of:

As used herein, the terms “carbocycle”, “carbocyclic” or “carbocyclyl”refer to a substituted or unsubstituted, stable monocyclic or bicyclichydrocarbon ring system which is saturated, partially saturated orunsaturated, and contains from 3 to 10 ring carbon atoms. Accordinglythe carbocyclic group may be aromatic or non-aromatic, and includes thecycloalkyl and aryl compounds defined herein. The bonds connecting theendocyclic carbon atoms of a carbocyclic group may be single, double,triple, or part of a fused aromatic moiety.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated mono- or bicyclic alkyl ring system containing 3 to 10 carbonatoms. A designation such as “C₅-C₇ cycloalkyl” refers to a cycloalkylradical containing from 5 to 7 ring carbon atoms. Preferred cycloalkylgroups include those containing 5 or 6 ring carbon atoms. Examples ofcycloalkyl groups include such groups as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexl, cycloheptyl, cyclooctyl, pinenyl, andadamantanyl.

As used herein, the term “aryl” refers to a substituted orunsubstituted, mono- or bicyclic hydrocarbon aromatic ring system having6 to 12 ring carbon atoms. Examples include phenyl and naphthyl.Preferred aryl groups include unsubstituted or substituted phenyl andnaphthyl groups. Included within the definition of “aryl” are fused ringsystems, including, for example, ring systems in which an aromatic ringis fused to a cycloalkyl ring. Examples of such fused ring systemsinclude, for example, indane, indene, and tetrahydronaphthalene.

As used herein, the terms “heterocycle”, “heterocyclic” or“heterocyclyl” refer to a substituted or unsubstituted carbocyclic groupin which the ring portion includes at least one heteroatom such as O, N,or S. The nitrogen and sulfur heteroatoms may be optionally oxidized,and the nitrogen may be optionally substituted in non-aromatic rings.Heterocycles are intended to include heteroaryl and heterocycloalkylgroups.

As used herein, the term “heterocycloalkyl” refers to a cycloalkyl groupin which one or more ring carbon atoms are replaced by at least onehetero atom such as —O—, —N—, or —S—. Examples of heterocycloalkylgroups include pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,pyrazolidinyl, pyrazolinyl, pyrazalinyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydrofuranyl, dithiolyl, oxathiolyl,dioxazolyl, oxathiazolyl, pyranyl, oxazinyl, oxathiazinyl, andoxadiazinyl.

As used herein, the term “heteroaryl” refers to an aromatic groupcontaining 5 to 10 ring carbon atoms in which one or more ring carbonatoms are replaced by at least one hetero atom such as —O—, —N—, or —S—.Examples of heteroaryl groups include pyrrolyl, furyl, thienyl,pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl,oxathiolyl, oxadiazolyl, triazolyl (including 1,2,3 triazolyl, 1,2,4triazolyl, and 3-oxo-1,2,4 triazolyl), oxatriazolyl, furazanyl,tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,picolinyl, indolyl, isoindolyl, indazolyl, benzofuranyl,isobenzofuranyl, purinyl, quinazolinyl, quinolyl, isoquinolyl,benzoimidazolyl, benzothiazolyl, benzothiophenyl, thianaphthenyl,benzoxazolyl, benzisoxazolyl, cinnolinyl, phthalazinyl, naphthyridinyl,and quinoxalinyl. Included within the definition of “heteroaryl” arefused ring systems, including, for example, ring systems in which anaromatic ring is fused to a heterocycloalkyl ring. Examples of suchfused ring systems include, for example, phthalamide, phthalicanhydride, indoline, isoindoline, tetrahydroisoquinoline, chroman,isochroman, chromene, and isochromene.

As used herein, the term “arylalkyl” refers to an alkyl group that issubstituted with an aryl group. Examples of arylalkyl groups include,but are not limited to, benzyl, bromobenzyl, phenethyl, benzhydryl,diphenylmethyl, triphenylmethyl, diphenylethyl, naphthylmethyl, etc.

As used herein, the term “spirocycloalkyl” refers to a cycloalkyl groupbonded to a carbon chain or carbon ring moiety by a carbon atom commonto the cycloalkyl group and the carbon chain or carbon ring moiety. Forexample, a C₃ alkyl group substituted with an R group wherein the Rgroup is spirocycloalkyl containing 5 carbon atoms refers to:

As used herein, the term “amino acid” refers to a group containing bothan amino group and a carboxyl group. Embodiments of amino acids includeα-amino, β-amino, γ-amino acids. The α-amino acids have a generalformula HOOC—CH(side chain)-NH₂. In certain embodiments, substituentgroups for the compounds of the present invention include the residue ofan amino acid after removal of the hydroxyl moiety of the carboxyl groupthereof, i.e., groups of formula —C(═O)CH(NH₂)−(side chain). The aminoacids can be in their D, L or racemic configurations. Amino acidsinclude naturally-occurring and non-naturally occurring moieties. Thenaturally-occurring amino acids include the standard 20 α-amino acidsfound in proteins, such as glycine, serine, tyrosine, proline,histidine, glutamine, etc. Naturally-occurring amino acids can alsoinclude non-α-amino acids (such as β-alanine, γ-aminobutyric acid,homocysteine, etc.), rare amino acids (such as 4-hydroxyproline,5-hydroxylysine, 3-methylhistidine, etc.) and non-protein amino acids(such as citrulline, ornithine, canavanine, etc.). Non-naturallyoccurring amino acids are well-known in the art, and include analogs ofnatural amino acids. See Lehninger, A. L. Biochemistry, 2^(nd) ed.;Worth Publishers: New York, 1975, pp. 71-77, the disclosure of which isincorporated herein by reference. Non-naturally occurring amino acidsalso include α-amino acids wherein the side chains are replaced withsynthetic derivatives. Representative side chains of naturally occurringand non-naturally occurring α-amino acids are shown below in Table A.TABLE A H CH₃ CH(CH₃)₂ CH₂CH(CH₃)₂ CH(CH₃)CH₂CH₃ CH₂OH CH₂SH CH(OH)CH₃CH₂CH₂SCH₃ CH₂C₆H₅ (CH₂)₄NH₂ (CH₂)₃NHC(═NH)NH₂ CH₂COOH CH₂CH₂COOHCH₂CONH₂ CH₂CH₂CONH₂ CH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₂CH₃ CH₂CH₂SH CH₂CH₂OHCH₂CH₂SCH₃ (CH₂)₃NH₂ (CH₂)₂CH(OH)CH₂NH₂ (CH₂)₃NHC(═O)NH₂(CH₂)₂ONHC(═NH)NH₂ CH₂C(═O)NHCH₂COOH

As used herein, the term “subject” refers to a warm blooded animal suchas a mammal, preferably a human, or a human child, which is afflictedwith, or has the potential to be afflicted with one or more diseases andconditions described herein.

As used herein, a “therapeutically effective amount” refers to an amountof a compound of the present invention effective to prevent or treat thesymptoms of particular disorder. Such disorders include, but are notlimited to, those pathological and neurological disorders associatedwith the aberrant activity described herein, wherein the treatment orprevention comprises inhibiting, inducing, or enhancing the activitythereof by contacting the receptor with a compound of the presentinvention.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem complicationscommensurate with a reasonable benefit/risk ratio.

As used herein, the term “unit dose” refers to a single dose which iscapable of being administered to a patient, and which can be readilyhandled and packaged, remaining as a physically and chemically stableunit dose comprising either the active compound itself, or as apharmaceutically acceptable composition, as described hereinafter.

All other terms used in the description of the present invention havetheir meanings as is well known in the art.

In another aspect, the present invention is directed to pharmaceuticallyacceptable salts of the compounds described above. As used herein,“pharmaceutically acceptable salts” includes salts of compounds of thepresent invention derived from the combination of such compounds withnon-toxic acid or base addition salts.

Acid addition salts include inorganic acids such as hydrochloric,hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acid, as wellas organic acids such as acetic, citric, propionic, tartaric, glutamic,salicylic, oxalic, methanesulfonic, para-toluenesulfonic, succinic, andbenzoic acid, and related inorganic and organic acids.

Base addition salts include those derived from inorganic bases such asammonium and alkali and alkaline earth metal hydroxides, carbonates,bicarbonates, and the like, as well as salts derived from basic organicamines such as aliphatic and aromatic amines, aliphatic diamines,hydroxy alkamines, and the like. Such bases useful in preparing thesalts of this invention thus include ammonium hydroxide, potassiumcarbonate, sodium bicarbonate, calcium hydroxide, methylamine,diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and thelike.

In addition to pharmaceutically-acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of the compounds, in the preparation of other salts, or inthe identification and characterization of the compounds orintermediates.

The pharmaceutically acceptable salts of compounds of the presentinvention can also exist as various solvates, such as with water,methanol, ethanol, dimethylformamide, ethyl acetate and the like.Mixtures of such solvates can also be prepared. The source of suchsolvate can be from the solvent of crystallization, inherent in thesolvent of preparation or crystallization, or adventitious to suchsolvent. Such solvates are within the scope of the present invention.

The present invention also encompasses the pharmaceutically acceptableprodrugs of the compounds disclosed herein. As used herein, “prodrug” isintended to include any compounds which are converted by metabolicprocesses within the body of a subject to an active agent that has aformula within the scope of the present invention. Since prodrugs areknown to enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.) the compounds of thepresent invention may be delivered in prodrug form. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Prodrugs, Sloane, K. B., Ed.;Marcel Dekker: New York, 1992, which is incorporated herein by referencein its entirety.

It is recognized that compounds of the present invention may exist invarious stereoisomeric forms. As such, the compounds of the presentinvention include all stereoisomeric forms, such as the diastereomericand enantiomeric forms. The compounds are normally prepared as racematesand can conveniently be used as such, but individual stereoisomers canbe isolated or synthesized by conventional techniques if so desired.Such stereoisomeric forms are included in the present invention,including the racemates, individual enantiomers and diastereomers, andmixtures thereof.

It is well known in the art how to prepare and isolate such opticallyactive forms. Specific stereoisomers can be prepared by stereospecificsynthesis using enantiomerically pure or enantiomerically enrichedstarting materials. The specific stereoisomers of either startingmaterials or products can be resolved and recovered by techniques knownin the art, such as resolution of racemic forms, normal, reverse-phase,and chiral chromatography, recrystallization, enzymatic resolution, orfractional recrystallization of addition salts formed by reagents usedfor that purpose. Useful methods of resolving and recovering specificstereoisomers described in Eliel, E. L.; Wilen, S. H. Stereochemistry ofOrganic Compounds; Wiley: New York, 1994, and Jacques, J, et al.Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, eachincorporated by reference herein in their entireties.

It is further recognized that functional groups present on the compoundsof the present invention may contain protecting groups. For example, theamino acid side chain substituents of the compounds of the presentinvention can be substituted with protecting groups such asbenzyloxycarbonyl or t-butoxycarbonyl groups. Protecting groups areknown per se as chemical functional groups that can be selectivelyappended to and removed from functionalities, such as hydroxyl groupsand carboxyl groups. These groups are present in a chemical compound torender such functionality inert to chemical reaction conditions to whichthe compound is exposed. Any of a variety of protecting groups may beemployed with the present invention. Preferred groups for protectinglactams include silyl groups such as t-butyldimethylsilyl (“TBDMS”),dimethoxybenzhydryl (“DMB”), acyl, benzyl (“Bn”), and methoxybenzylgroups. Preferred groups for protecting hydroxy groups include TBS,acyl, benzyl, benzyloxycarbonyl (“CBZ”), t-butyloxycarbonyl (“Boc”), andmethoxymethyl. Many other standard protecting groups employed by oneskilled in the art can be found in Greene, T. W. and Wuts, P. G. M.,“Protective Groups in Organic Synthesis” 2d. Ed., Wiley & Sons, 1991.

Synthesis and Examples

The compounds of the present invention may be prepared in a number ofmethods well known to those skilled in the art, including, but notlimited to those described below, or through modifications of thesemethods by applying standard techniques known to those skilled in theart of organic synthesis. The reagents and starting materials arecommercially available, or readily synthesized by well-known techniquesby one of ordinary skill in the arts. All substituents in the syntheticschemes, unless otherwise indicated, are as previously defined. Allprocesses disclosed in association with the present invention arecontemplated to be practiced on any scale, including milligram, gram,multigram, kilogram, multikilogram or commercial industrial scale.

Illustrative of compounds encompassed by the present invention that areuseful in the utilities disclosed herein include those set forth in thefollowing tables. This list is meant to be representative only and isnot intended to limit the scope of the invention in any way. TABLE 1

Com- pound No. q X R Y MS I-1 0 bond CH₃ CH₂CONH₂ 292 (M + Na) I-2 0bond CH₃ CH₂CON(CH₃)₂ 298 (M + H) I-3 0 bond CH₃ CH₂CONH-(s)- 341CH(Me)CONH₂ (M + H) I-4 0 bond CH₃

346 (M + Na) I-5 0 bond C₂H₅ CH₂CONH₂ 306 (M + Na) I-6 0 bond C₂H₅

360 (M + Na) I-7 1 bond CH₃ CH₂CONH₂ 308 (M + Na) I-8 1 bond C₂H₅CH₂CONH₂ 322 (M + Na) I-9 1 bond CH₃ CH₂CON(CH₃)₂ 314 (M + H) I-10 1bond CH₃ CH₂CONHCH(CH₃)CONH₂ 357 (M + H) I-11 1 bond CH₃

362 (M + Na) I-12 1 bond C₂H₅

376 (M + Na) I-13 1 not CH₃ CH₂CONH₂ 310 present (M + Na) II- 1 0 bond H(CH₂)₂-N-morpholinyl 312 (M + H) II-2 1 bond H (CH₂)₂-N-morpholinyl 328(M + H) II-3 1 bond H (CH₂)₂-N-pyrrolidinyl 312 (M + H) II-4 1 bond H(CH₂)₂-N-piperidinyl 326 (M + H) II-5 0 bond H (CH₂)₂NH₂ 242 (M + H)II-6 0 bond H (CH₂)₂NHSO₂CH₃ 320 (M + H) II-7 1 bond H (CH₂)₂NHSO₂CH₃336 (M + H) II-8 1 bond H (CH₂)₂NHCOCH₃ 300 (M + H) II-9 1 bond HCH₂CH═CH₂ 255 (M + H) II-10 1 bond H CH₂C(Me)═CH₂ 269 (M + H) II-11 0bond H CH₂CH(CH₃)₂ 255 (M + H) II-12 1 bond H CH₂CH(CH₃)₂ 271 (M + H)II-13 0 bond H C₃H₇ 241 (M + H) II-14 1 bond H C₃H₇ 257 (M + H) II-15 1bond H CH₃ 229 (M + H) II-16 1 not H CH₃ 231 present (M + H) II-17 1bond H CH₂CN 254 (M + H) II-18 0 bond CH₃ CH₃ 227 (M + H) II-19 1 bondCH₃ CH₃ 243 (M + H)

Compounds of the present invention can be generated following varioussynthetic protocols as shown below.

General Synthetic Procedure for Compounds P2, P3, and P4:

Synthesis of compound P4 could be initiated from compound P. Thus,compound P is converted to corresponding hydroxyl compound P1 byreaction with an alkyl magnesium halide (RMgX) reagent. Compound P1could then be reacted with a thiol compound (containing a terminalcarbalkoxy group), in presence of an organic acid, e.g. trifluoroaceticacid, to generate compound P2. Conversion of compound P2 to compound P3via the intermediacy of a carboxylic acid moiety could be affected bybasic hydrolysis with LiOH followed by amidation reaction. Oxidation ofcompound P3 by an appropriate agent e.g. hydrogen peroxide in acidicmedium or m-chloroperbenzoic acid in an organic solvent producescompound P4.

Preparation of Compound B

To a stirring solution of compound A (5 g, 27.7 mmol) in dry THF (60 mL)at 0° C., under N₂, was added MeMgBr (3M in diethyl ether, 9.24 mL). Thecooling bath was removed and the mixture was stirred for an additional1.5 h. More MeMgBr (0.8 ml) was added to the reaction mixture followedby additional stirring for another 3 h. The reaction was carefullyquenched with ice-water and extracted into ethyl acetate (3×100 mL). Thecombined organic layers were washed with brine (1×50 mL), dried (MgSO₄),and concentrated to yield compound B (4.76 g): ¹H-NMR (DMSO-d₆) δ 7.73(d, 2H), 7.53 (dd, 2H), 7.36-7.28 (m, 4H), 5.51 (s, 1H), 1.57 (s, 3H).

Preparation of Compound B1

This compound was prepared following the similar procedure as describedpreviously for the synthesis of compound B, except that EtMgBr was usedin place of MeMgBr. Thus, starting with 5 g of compound A, 2.69 g ofcompound B1 was obtained: ¹H-NMR (DMSO-d₆) δ 7.73 (d, 2H), 7.47 (d, 2H),7.36-7.27 (m, 4H), 5.51 (s, 3H), 2.02 (q, 2H), 0.42 (t, 3H).

Preparation of Compound C

A mixture of compound B (1.5 g, 7.6 mmol), methyl thioglycolate (0.68mL, 7.6 mmol) and trifluoroacetic acid (0.58 mL, 7.6 mmol) in CH₂Cl₂ (15mL) was stirred at room temperature for 18 h, quenched with sat. sodiumbicarbonate and extracted into CH₂Cl₂ (3×50 mL). The combined organiclayers were washed with brine (1×50 mL), dried (MgSO₄) and concentratedto give a crude product that was purified by silica gel columnchromatography (hexane:ethyl acetate::8:1) to yield 1.8 g of product asa pale yellow solid: ¹H-NMR (DMSO-d₆) δ 7.84-7.82 (m, 2H), 7.57-7.55 (m,2H), 7.41-7.34 (m, 4H), 3.21 (s, 3H), 2.58 (s, 2H), 1.71 (s, 3H).

Preparation of Compound C1

This compound was prepared following the similar procedure as describedpreviously for the synthesis of compound C, except that compound B1 wasused in place of compound B. Thus, starting with 2.68 g of compound B1,3.7 g of product was obtained: ¹H-NMR (DMSO-d₆) δ 7.84-7.82 (m, 2H),7.51-7.49 (m, 2H), 7.41-7.34 (m, 4H), 3.21 (s, 3H), 2.58 (s, 2H), 2.23(q, 2H), 0.35 (t, 3H).

Preparation of Compound D

To a solution of compound C (0.5 g, 1.75 mmol) in methanol (6 mL) atroom temperature was added LiOH.H₂O (0.088 g, 2.1 mmol) in water (2 mL).The reaction mixture was stirred at this temperature for 3 h and then at60° C. for 1 h. It was then concentrated, diluted with water (20 mL),washed with diethyl ether (2×15 mL), acidified (pH ˜2) with 2N HCl andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (1×20 ml), dried (MgSO₄) and concentrated in vacuo togive 0.41 g of product: ¹H-NMR (CDCl₃): δ 9.30 (bs, 1H), 7.70 (d, 2H),7.60 (d, 2H), 7.30 (m, 4H), 2.50 (s, 2H), 1.80 (s, 3H).

EXAMPLE I-1

Synthesis of Compound I-1 (Compound E, wherein NR₁R₂=NH₂)

To a refluxing solution of compound D (2.35 g, 8.6 mmol) in benzene (18mL) was added thionyl chloride (2.6 mL, 34.7 mmol) dropwise. Thereaction mixture was heated for 1 h, concentrated in vacuo, dissolved indichloromethane (50 mL) and treated with 28% NH₄OH (10 mL) at roomtemperature. The mixture was vigorously stirred for 1 h and the layerswere separated. The aqueous layer was extracted with dichloromethane(1×50 mL). The combined organic layers were washed with water (2×20 mL),brine (1×20 ml), dried (MgSO₄), and concentrated to give a residue thaton trituration with ether generated 1.54 g of product: ¹H-NMR (CDCl₃): δ7.70 (d, 2H), 7.60 (d, 2H), 7.30 (m, 4H), 5.80 (bs, 1H), 5.10 (bs, 1H),2.50 (s, 2H), 1.80 (s, 3H).

EXAMPLE I-2

Synthesis of Compound I-2 (Compound E, wherein NR₁R₂=NMe₂)

This compound was prepared following the similar procedure as describedin Example I-1 wherein dimethylamine gas was used in place of 28% NH₄OHin the amidation step and the final product was purified by silica gelcolumn chromatography (ethyl acetate:hexanes::1:1). Thus, starting from2.3 g of compound D, 1.8 g of product was obtained: ¹H-NMR (CDCl₃): δ7.70-7.60 (m, 4H), 7.30 (m, 4H), 2.70 (s, 3H), 2.60 (s, 3H), 2.50 (s,2H), 1.80 (s, 3H).

EXAMPLE I-3

Synthesis of Compound I-3 (Compound E, wherein NR₁R₂=NH-(s)-CH(Me)CONH₂)

To a solution of compound D (2 g, 7.35 mmol) in DMF (10 mL) at roomtemperature was successively added2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(“TBTU”)(1.2 eqv) and N-methylmorpholine (“NMM”)(1 mL). The mixture wasstirred for 10 min, treated dropwise with a mixture of alaninehydrochloride (1.37 g, 11 mmol) and NMM (2 mL) in DMF (15 ml) andstirred overnight. The reaction mixture was then diluted with water andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (3×20 mL), brine (1×20 mL), dried (MgSO₄) andconcentrated to give a crude solid that, on trituration with ether,generated 2.50 g of product: ¹H-NMR (DMSO-d₆): δ 7.60-7.10 (m, 8H), 7.00(s, 1H), 6.80 (s, 1H), 3.70 (m, 1H), 2.30 (m, 2H), 2.20 (s, 1H), 1.50(s, 3H), 0.80 (d, 3H).

EXAMPLE I-4

Synthesis of Compound I-4 (Compound E, wherein NR₁R₂=N-pyrrolidinyl)

A mixture of compound C (1.76 g, 6.2 mmol), pyrrolidine (2.58 mL, 31mmol) and methanol (10 mL) was stirred at room temperature for 65 h andconcentrated to generate a crude product that was purified by silica gelcolumn chromatography (hexane:ethyl acetate::1:1) to yield 1.32 g ofproduct: ¹H-NMR (DMSO-d₆) δ 7.85-7.83 (m, 2H), 7.62-7.60 (m, 2H),7.42-7.35 (m, 4H), 3.00 (t, 2H), 2.83 (t, 2H), 2.54 (s, 2H), 1.72 (s,3H), 1.69-1.59 (m, 4H).

EXAMPLE I-5

Synthesis of Compound I-5 (Compound E1, wherein NR₁R₂=NH₂)

A mixture of compound C1 (1.24 g, 4.2 mmol), methanol (5 mL) and NH₃ gaswas maintained at 50° C. in a sealed tube for 20 h, cooled to roomtemperature, recharged with NH₃ gas and kept at 50° C. for an additional20 h. The reaction mixture was then concentrated and triturated withether to yield 0.94 g of product. This material was used in the nextstep without any further purification: ¹H-NMR (DMSO-d₆) δ 7.86-7.82 (m,2H), 7.65-7.52 (2H), 7.42-7.35 (m, 4H), 7.12 (br s, 1H), 6.83 (br s,1H), 2.48 (s, 2H), 2.25 (q, 2H), 0.35 (t, 3H).

EXAMPLE I-6

Synthesis of Compound I-6 (Compound E1, wherein NR₁R₂=N-pyrrolidinyl)

This compound was prepared following the similar procedure as describedpreviously in Example I-5 wherein pyrrolidine was used in place of 28%NH₄OH in the amidation step that was carried out at room temperature andthe final product was purified by silica gel column chromatography(ethyl acetate:hexanes::1:1). Thus, starting from 1.29 g of compoundI-2, 1.38 g of product was obtained: ¹H-NMR (DMSO-d₆) δ 7.86-7.83 (m,2H), 7.56-7.54 (m, 2H), 7.41-7.35 (m, 4H), 3.01 (t, 2H), 2.84 (t, 2H),2.24 (q, 2H), 2.50 (m, 2H), 1.68-1.59 (m, 4H), 0.37 (t, 3H).

EXAMPLE I-7

Synthesis of Representative Compound I-7 (Compound F, wherein NR₁R₂=NH₂)

A mixture of compound I-1 (1.18 g, 4.3 mmol) in gl. acetic acid (10 mL)and 50% aqueous H₂O₂ (1.1 eqv) was stirred at room temperature 2 h,treated with additional peroxide (0.2 eqv) and stirred for another 1 h.It was then diluted with water (20 mL) and extracted with ethyl acetate(3×75 mL). The combined organic layers were washed with 2% aq. sodiumbicarbonate (2×10 mL), water (1×10 mL), and brine (1×10 mL), dried(MgSO₄), and concentrated to give a crude solid that on trituration withether generated 1.09 g of product: ¹H-NMR (DMSO-d₆): δ 7.80 (t, 2H),7.50-7.30 (m, 7H), 6.90 (b, H), 2.10-1.90 (q, 2H), 1.80 (s, 3H).

EXAMPLE I-8

Synthesis of Compound I-8 (Compound F1, wherein NR₁R₂=NH₂)

Compound I-5 was oxidized to give the product following the sameprocedure as described in Example I-7; ¹H-NMR (DMSO-d₆): δ 8.00 (m, 2H),7.50 (m, 6H), 7.40 (d, 1H), 7.10 (d, 1H), 2.50 (m, 2H), 2.20 (dd, 2H),0.50 (t, 3H).

EXAMPLE I-9

Synthesis of Compound I-9 (Compound F, wherein NR₁R₂=NMe₂)

Compound I-2 was oxidized to give the product following the sameprocedure as described in Example I-7; ¹H-NMR (DMSO-d₆): δ 8.20-7.50(series of m, 8H), 2.80 (s, 3H), 2.50 (s, 3H), 2.60-2.30 (2 d, 2H), 2.10(s, 3H).

EXAMPLE I-10

Synthesis of Compound I-10 (Compound F, whereinNR₁R₂=NH-(s)-CH(Me)CONH₂)

Compound I-3 was oxidized to give the product (mixture of diastereomers)following the same procedure as described in Example I-7; ¹H-NMR(DMSO-d₆): δ 8.40-7.50 (m, 8H), 7.40-6.80 (2 sets of d, 2H), 4.00 (m,1H), 3.20 (q, 1H), 2.50-2.30 (m, 2H), 1.80 (s, 3H), 1.10 (m, 3H).

EXAMPLE I-11

Synthesis of Compound I-11 (Compound F, wherein NR₁R₂=N-pyrrolidinyl)

Compound I-4 was oxidized to give the product following the sameprocedure as described in Example I-7; ¹H-NMR (DMSO-d₆): δ 8.00 (m, 2H),7.50 (m, 6H), 3.10-2.70 (series of m, 4H), 2.20 (dd, 2H), 1.90 (s, 3H),1.70 (m, 4H).

EXAMPLE I-12

Synthesis of Compound I-12 (Compound F1, wherein NR₁R₂=N-pyrrolidinyl)

Compound I-6 was oxidized to give the product following the sameprocedure as described in Example I-7; ¹H-NMR (DMSO-d₆): δ 8.00 (m, 2H),7.50 (m, 6H), 3.10 (m, 2H), 2.70 (m, 4H), 2.20 (dd, 2H), 1.70 (m, 4H),0.50 (t, 3H).

EXAMPLE I-13

Synthesis of Compound I-13

Starting with benzophenone in place of compound A in Scheme I, theproduct was prepared following the same multi-step synthetic sequence asdescribed in the previous examples; ¹H-NMR (DMSO-d₆): δ 7.50 (b, 1H),7.40-7.20 (m, 10H), 7.10 (b, 1H), 2.80 (dd, 2H), 1.80 (s, 3H).

General Synthetic Procedure for Compounds in General Scheme B:

Synthesis of various compounds can be initiated from compound P1. Thus,compound P1 is converted to corresponding compound S1 by reaction withthiourea in an acidic medium e.g. HBr. Compound S1 could then behydrolyzed to corresponding thiol compound T1 in a basic hydrolysisstep. In situ alkylation of compound T1 by an appropriate alkylatingagent containing a terminal amino group generates compound U1 that couldfurther be derivatized in the amino position in subsequent steps.Oxidation of compound U1 by an appropriate agent e.g. hydrogen peroxidein acidic medium or m-chloroperbenzoic acid produces compound V1.

Preparation of Compound bb

Synthesis of compound bb had been disclosed in U.S. Pat. No. 6,492,396which is incorporated herein by reference in its entirety.

EXAMPLE II-1

Synthesis of Compound II-1

To a mixture of compound bb (2.13 g, 6.89 mmol) in water (5 mL) at 70°C. was added a mixture of 4-(2-chloroethyl)morpholine hydrochloride(1.53 g, 8.2 mmol) in water (5 mL) and 10N NaOH (3 mL). The reactionmixture was heated at 110° C. for 1 h, cooled and extracted into ether(3×50 mL). The combined organic layers were washed with water (1×15 mL),brine (1×15 ml), dried (MgSO₄) and concentrated to generate a crudeproduct that was purified by flash chromatography (silica gel;solvent:ethyl acetate:hexane::2:3) to yield 1.48 g of compound II-1:¹H-NMR (CDCl₃): δ 7.70 (m, 4H), 7.30 (m, 4H), 4.90 (s, 1H), 3.50 (m,4H), 2.20-1.90 (m, 8H).

EXAMPLE II-2

Synthesis of Compound II-2

To a cooled (−15° C.) solution of compound II-1 (1.45 g, 4.66 mmol) indichloromethane (15 mL) was added m-chloroperbenzoic acid (77%, 0.8 g,4.66 mmol) in portions. The reaction mixture was stirred for 1 h,quenched with 2% aq. sodium bicarbonate (50 ml), and diluted withdichloromethane (100 ml). The separated organic layers were washed with2% aq. sodium bicarbonate (2×20 ml), water (1×20 mL), and brine (1×20ml), dried (MgSO₄), filtered and concentrated to give a crude product.It was purified by flash chromatography (silica gel; ethyl acetatefollowed by methanol:dichloromethane::5:95) to yield an oil that ontrituration with ether generated 0.067 g of compound II-2: ¹H-NMR(CDCl₃): δ 7.90-7.70 (m, 3H), 7.60-7.30 (m, 5H), 5.40 (s, 1H), 3.60 (m,3H), 2.50 (m, 1H), 2.30-2.20 (m, 5H), 1.80-1.60 (m, 3H).

EXAMPLE II-3

Synthesis of Compound II-3

This compound was prepared following the same procedure as described inExamples II-1 and II-2, except that terminal morpholinyl group wasreplaced by a pyrrolidinyl group; ¹H-NMR (CDCl₃): δ 8.00-7.30 (series ofm, 8H), 5.60 (s, 1H), 3.20-2.40 (series of broad m, 8H), 1.70 (broad,4H).

EXAMPLE II-4

Synthesis of Compound II-4

This compound was prepared following the same procedure as described inExamples II-1 and II-2, except that terminal morpholinyl group wasreplaced by a piperidinyl group; ¹H-NMR (CDCl₃): δ 8.10-7.30 (series ofm, 8H), 5.60 (s, 1H), 3.20-2.40 (series of broad m, 8H), 1.70 (broad,4H), 1.60 (broad, 2H).

EXAMPLE II-5

Synthesis of Compound II-5

This compound was prepared following the same procedure as described inExample II-1 wherein 2-chloroethylamine hydrochloride was used in placeof 4-(2-chloroethyl)morpholine hydrochloride as one of the reactants.This material was directly used in the next step.

EXAMPLE II-6

Synthesis of Compound II-6

To a mixture of compound II-5 (0.73 g, 3.04 mmol) and triethylamine(0.47 ml, 3.4 mmol) in dichloromethane (10 mL) at 0° C. was addedmethanesulfonyl chloride (0.26 mL, 3.35 mmol). The cooling bath wasremoved and the reaction mixture was stirred at room temperature for 1h, treated with 2N HCl (20 mL) and extracted into dichloromethane (2×25mL). The combined organic layers were washed with water (1×10 mL), brine(1×10 mL), dried (MgSO₄) and concentrated to give 0.97 g of compoundII-6 that was immediately taken into next step.

EXAMPLE II-7

Synthesis of Compound II-7

To a mixture of compound II-6 (0.97 g, 3.03 mmol) in glacial acetic acid(10 mL) at room temperature was added H₂O₂ (50% in water, 0.247 mL). Themixture was stirred for 0.5 h, diluted with ice-water (100 mL) andstirred for an additional 0.5 h. The separated solid was filtered andwashed several times with water and ether successively, and dried underhigh vacuum to generate 0.56 g of compound II-7: ¹H-NMR (DMSO-d₆): δ7.80 (t, 2H), 7.60 (d, 1H), 7.50 (d, 1H), 7.30 (m, 2H), 7.20 (m, 3H),5.50 (s, 1H), 2.90 (m, 2H), 2.60 (s, 3H), 1.90 (m, 2H).

EXAMPLE II-8

Synthesis of Compound II-8

This compound was prepared following the same synthetic scheme asdescribed in Examples II-6 and II-7 except that an acetamido group wasemployed at the terminus; ¹H-NMR (DMSO-d₆): δ 8.10-7.30 (series of m,8H), 5.60 (s, 1H), 3.30 (s, 1H), 3.20 (m, 2H), 2.10 (m, 2H), 1.80 (s,3H).

General Synthetic Procedure for Compounds in General Scheme C

Synthesis of compound V2 could be initiated from compound T1. Thus,alkylation of compound T1 by an appropriate alkylating agent in presenceof a base generates compound U2 that on oxidation by an appropriateagent e.g. hydrogen peroxide in acidic medium or m-chloroperbenzoic acidproduces compound V2.

EXAMPLE II-9

Synthesis of Compound II-9 (Compound ee wherein R=—CH₂CH═CH₂)

A mixture of compound bb (14.12 g, 44 mmol), 10 N NaOH (14.9 mL) andwater (109 mL) was heated at 70° C. for 0.5 h, cooled, diluted withice-water, acidified (pH 2) and extracted into ethyl acetate (3×100 mL).The combined organic layers were washed with water (1×50 mL) and brine(1×50 mL), dried (MgSO₄) and concentrated to yield 9.45 g of compound ccthat was directly taken into next step without any further purification;¹H-NMR (DMSO-d₆) δ 7.89 (d, 2H), 7.76 (d, 2H), 7.43 (m, 4H), 5.21 (d,1H), 3.55 (d, 1H).

Thus, a mixture of compound cc (2 g, 10.1 mmol) in methanol (16 mL) andsodium methoxide (0.5 M in methanol, 20.2 mL) was heated at 60° C. for0.5 h, treated with allyl iodide (4.66 mL, 50.5 mmol), continued heatingfor an additional 0.5 h, cooled, and quenched with ice-water. It wasthen acidified (pH 2) and extracted into ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (1×50 mL) and brine (1×50mL), dried (MgSO₄) and concentrated to yield a crude material. Thismaterial was stirred in pet. ether (20 mL) and filtered. The filtrate,upon concentration, provided 1.97 g of compound dd (R=—CH₂CH═CH₂) whichwas oxidized by 50% H₂O₂ to give compound II-9 following the previouslydescribed procedure in Example I-10; ¹H-NMR (DMSO-d₆) δ 8.00-7.20(series of m, 8H), 5.60 (s, 1H), 5.50 (m, 1H), 5.50 (m, 2H), 2.90 (m,2H).

EXAMPLE II-10

Synthesis of Compound II-10 (Compound ee wherein R=—CH₂C(Me)═CH₂)

This compound was prepared following the same scheme as in Example II-9,except that a 2-methyl propylene group was employed at the terminus;¹H-NMR (DMSO-d₆) δ 8.00-7.20 (series of m, 8H), 5.60 (s, 1H), 4.90 (s,1H), 4.60 (s, 1H), 2.60 (dd, 2H), 1.50 (s, 3H).

EXAMPLE II-11

Synthesis of Compound II-11 (Compound dd wherein R=—CH₂CHMe₂)

A mixture of compound cc (2 g, 10.1 mmol) in methanol (16 mL) and sodiummethoxide (0.5 M in methanol, 20.2 mL) was heated at 60° C. for 0.5 h,treated with 1-iodo-2-methylpropane (6 mL, 50.5 mmol), heated for anadditional 0.5 h, cooled, and quenched with ice-water. It was thenacidified (pH ˜2) and extracted into ethyl acetate (3×50 mL). Thecombined organic layers were washed with water (1×50 mL) and brine (1×50mL), dried (MgSO₄) and concentrated to yield a crude material. Thismaterial was stirred in pet. ether (20 mL) and filtered. The filtrate,upon concentration, provided 2.21 g of compound II-11 that was directlyused in the next step: ¹H-NMR (DMSO-d₆) δ 7.86 (d, 2H), 7.64 (d, 2H),7.42 (m, 4H), 5.13 (s, 1H), 1.90 (d, 2H), 1.36 (m, 1H), 0.74 (s, 3H),0.72 (s, 3H).

EXAMPLE II-12

Synthesis of Compound II-12 (Compound ee wherein R=—CH₂CHMe₂)

To a cooled (ice-bath) solution of compound II-11 (1 g, 3.9 mmol) in gl.acetic acid (4 mL) was added 50% H₂O₂ (0.27 mL). The reaction mixturewas stirred for 1 h, diluted with ethyl acetate and concentrated to givea crude product that was purified by flash chromatography (silica,solvent-gradient:hexane:ethyl acetate::4:1 to ethyl acetate) to generate0.71 g of compound II-12: ¹H-NMR (DMSO-d₆) δ 7.97 (t, 2H), 7.73 (d, 1H),7.63 (d, 1H), 7.52 (m, 2H), 7.38 (m, 2H), 5.60 (s, 1H), 1.89 (dd, 1H),1.76 (m, 1H), 1.66 (dd, 1H), 0.78 (d, 3H), 0.76 (d, 3H).

EXAMPLE II-13

Synthesis of Compound II-13 (Compound dd wherein R=C₃H₇)

This compound was prepared following the same procedure as describedbefore for the synthesis of compound II-11, except that n-propyl iodidewas utilized as an alkylating agent. It was immediately used in thesynthesis of compound II-14.

EXAMPLE II-14

Synthesis of Compound II-14 (Compound ee wherein R=C₃H₇)

Utilizing compound II-13, this compound was prepared following the sameprocedure as described before for the synthesis of compound II-12;¹H-NMR (DMSO-d₆) δ 8.00-7.20 (series of m, 8H), 5.60 (s, 1H), 1.90 (2sets of m, 2H), 1.50 (m, 2H), 0.80 (t, 3H).

EXAMPLE II-15

Synthesis of Compound II-15 (Compound ee wherein R=CH₃)

This compound had been described by: Kice, J. L., Lotey, H. J. Org.Chem. 1988, 53, 3593; this reference has been included herein in itsentirety.

EXAMPLE II-16

Synthesis of Compound II-16

This compound had been described by Mizuno, H., Matsuda, M., Ino, M. J.Org. Chem. 1981, 46, 520; this reference has been included herein in itsentirety.

EXAMPLE II-17

Synthesis of Compound II-14 (Compound ee wherein R=CH₂CN)

This compound had been described by: Kice, J. L., Lotey, H. J. Org.Chem. 1988, 53, 3593; this reference has been included herein in itsentirety.

EXAMPLE II-18

Synthesis of Compound II-18

To a cooled (−78° C.) solution of compound a (3.43 g, 19 mmol) inanhydrous THF (60 mL) was added n-butyl lithium in hexanes (2.5 M, 9.1mL, 23 mmol). The reaction mixture was stirred for an additional 0.5 h,treated with dimethyl disulfide (2.54 mL, 29 mmol) in two portions overa period of 0.5 h, and stirred for another 0.5 h. It was then quenchedwith ice-water (50 mL) and extracted into ethyl acetate (2×50 mL). Thecombined organic layers were washed with brine (1×50 mL), dried (MgSO₄)and concentrated to give a crude material that was purified bysilica-gel column chromatography (solvent:hexanes) to yield 3.33 g ofcompound II-18 (yellow solid): ¹H-NMR (DMSO-d₆) δ 7.85-7.82 (m, 2H),7.58-7.55 (m, 2H), 7.40-7.35 (m, 4H), 1.72 (s, 3H), 1.32 (s, 3H). Themethod was an adaptation from a procedure previously described in J MedChem 1986, 29, 1577, which is incorporated herein by reference in itsentirety.

EXAMPLE II-19

Synthesis of Compound II-19

To a cooled (−78° C.) solution of compound II-18 (3.32 g, 14.7 mmol) inCH₂Cl₂ (50 mL) was slowly added a solution of m-chloroperbenzoic acid(70-75%, 3.96 g) in CH₂Cl₂ (30 mL). The reaction mixture was stirred for2 h, treated with an additional 0.8 g of m-chloroperbenzoic acid, andstirred for another 2 h. It was then quenched with sat. NaHCO₃ (50 mL).The organic layer was separated and washed with sat. NaHCO₃ (2×50 mL),and water (1×50 mL), dried (MgSO₄) and concentrated to give a crudeproduct that was purified by silica gel column chromatography (solventgradient: 4:1 hexane/ethyl acetate to 2:1 hexane/ethyl acetate) to yield3.06 g of compound II-19: ¹H-NMR (DMSO-d₆) δ 8.00-7.95 (m, 2H),7.60-7.38 (m, 6H), 1.91 (s, 3H), 1.40 (s, 3H).

Additional compounds encompassed by the present invention include thoseset forth in the following table. This list is meant to berepresentative only and is not intended to limit the scope of theinvention in any way. The reagents and starting materials arecommercially available, or readily synthesized by well-known techniquesby one of ordinary skill in the arts. All substituents in the syntheticSchemes, unless otherwise indicated, are as previously defined. TABLE 2

Compound No. R R′ q R^(A) R^(B) Q III-1 H H 0 H H SO₂NH₂ III-2 H H 1 H HSO₂NH₂ III-3 H H 1 H H COCH₃ III-4 H H 1 H H P(O)(O¹Pr)₂ III-5 H H 1 H HC(OH)₂CF₃ III-6 H H 1 H H CH₂OH III-7 H H 1 H H CH₂OCH₃ III-8 H H 1 H H2-Furyl III-9 H H 1 H H

III-10 H H 1 H H 2-thiophene III-11 4-F 4′-F 1 H H SO₂NH₂ III-12 4-F4′-F 1 H H COCH₃ III-13 4-F 4′-F 1 H H CH₂OH III-14 4-F 4′-F 1 H HCH₂OMe III-15 4-F 4′-F 1 H H CH₂O(CH₂)₂OMe IV-1 H H 0 H H CONHOMe IV-2 HH 1 H H CONHOMe IV-3 H H 1 H H CONHOEt IV-4 4-F 4′-F 1 H H CONHOMe V-1 HH 1 H H CO-2-thienyl V-2 H H 1 H H C(OH)Me₂ V-3 H H 1 H H C(OH)(C═CH)₂V-4 4-F 4′-F 1 H H C(OH)Me₂ V-5 4-F 4′-F 1 H H CH(OH)Me VI-1 H H 1 F FCH₂OH VI-2 H H 1 Me Me CMe₂OH VII-1 H H 0 Cyclohexyl CO₂CH₃ VII-2 H H 0Cyclohexyl CONH₂ VII-3 H H 1 Cyclohexyl CONH₂ VIII-1 H H 0 CyclopentylCONH₂ VIII-2 H H 1 Cyclopentyl CONH₂ IX-1 H H 0 Cyclobutyl CONH₂ IX-2 HH 1 Cyclobutyl CONH₂ IX-3 4-F 4′-F 1 Cyclobutyl CONH₂ X-1 H H 1Cyclopropyl CONH₂

-   Reagents for Step 1, compounds 31a and 31b: (i) 10 N NaOH/EtOH/70°    C.; (ii) compound 35, reflux 2 h. Step 2: 50% H₂O₂ in water/HOAc/RT    or m-chloroperbenzoic acid, dichloromethane, 0° C.-   Reagents for Step 1, compound 31c: NaH/DMF/compound 35/room    temperature to 70° C.    Preparation of Compounds 31 and 35

The preparation of compounds 31c (U.S. Pat. No. 4,066,686) and 35(El-Hewehi, Z.; Runge, F. J. Prakt. Chem. 1962, 16, 297) were describedin the literature, and both references are incorporated herein in theirentireties.

EXAMPLE III-1

Synthesis of Compound III-1

To a stirred mixture of NaH (60% in oil, 745 mg, 18.62 mmol) in dry DMF(15 mL) at room temperature and under argon was added dropwise asolution of compound 31c (3.33 g, 16.64 mmol) in dry DMF (3 mL). Themixture was stirred at room temperature for 15 min. The reaction mixturewas then treated with compound 35 (2.2 g, 16.98 mmol) followed byheating at 70° C. for 4 h. It was then cooled to room temperature,concentrated at high vacuum, diluted with water and extracted intoEtOAc. The combined organic layers were washed successively with waterand brine, dried (MgSO₄) and concentrated to give a crude product thatwas purified by flash chromatography (silica gel, hexane:EtOAc::3:2) toyield compound III-1 (3.9 g): ¹H-NMR (DMSO-d₆): δ 7.18-6.8 (series of m,11H), 6.65 (s, 1H), 5.25 (s, 1H), 2.90 (s, 2H).

EXAMPLE III-2

Synthesis of Compound III-2

To a solution of the compound III-1 (3.88 g, 13.24 mmol) in acetic acid(25 mL) was added hydrogen peroxide (50% solution in water, 910 μL). Thereaction mixture was stirred at room temperature overnight. Solvent wasremoved and the crude product was stirred in EtOAc, filtered and driedto generate compound III-2 (1.08 g) m.p.: 165-166° C., ¹H-NMR (DMSO-d₆):δ 7.54-7.35 (series of m, 12H), 5.52 (s, 1H), 4.23 (d, 1H), 3.93 (d,1H). MS: 331.91 (M+Na),

EXAMPLE III-3

Synthesis of Compound III-3

Utilizing compound 31c and chloroacetone in first step, compound III-3was synthesized; mp.: 81-82° C.; ¹H-NMR (DMSO-d₆): δ 7.56-7.32 (seriesof m, 10H), 5.34 (s, 1H), 3.66 (dd, 2H), 2.13 (s, 3H). MS: 294.99 (M+Na)

EXAMPLE III-4

Synthesis of Compound III-4

Utilizing compound 31c and diisopropylbromomethyl phosphonate in firststep, compound III-4 was synthesized; mp: 127-128° C., ¹H-NMR (DMSO-d₆):δ 7.53-7.34 (series of m, 10H), 5.42 (s, 1H), 4.58 (m, 2H), 2.94 (m,2H). MS: 394.79 (M+H).

EXAMPLE III-5

Synthesis of Compound III-5

Utilizing compound 31c and 3-bromo-1,1,1-trifluoro-propan-2-one in firststep, compound III-5 was synthesized; m.p.: 121-122° C.; ¹H-NMR(DMSO-d₆): δ 7.72-7.32 (series of m, 12H), 5.37 (s, 1H), 3.02 (d, 1H),2.69 (d, 1H). MS: 366.92 (M+Na).

EXAMPLE III-6

Synthesis of Compound III-6

Utilizing compound 31c and 2-chloroethoxytrimethylsilane in first step,compound III-6 was synthesized; mp.: 134° C., ¹H-NMR (DMSO-d₆): δ7.64-7.30 (series of m, 10H), 5.24 (s, 1H), 4.94 (m, 1H), 3.69 (m, 2H),2.64-2.49 (two sets of m, 2H). MS: 260.98 (M+H).

EXAMPLE III-7

Synthesis of Compound III-7

Utilizing compound 31c and bromoethylmethyl ether in first step,compound III-7 was synthesized; m.p.: 71-72° C.; ¹H-NMR (DMSO-d₆): δ7.52-7.31 (series of m, 10H), 5.21 (s, 1H), 3.51 (m, 2H), 3.31 (s, 3H),2.75-2.53 (two m, 2H). MS: 274.95 (M+H),

EXAMPLE III-8

Synthesis of Compound III-8

Utilizing furan-2-yl-methanethiol in place of 31a/b/c, andbromodiphenylmethane in step 1, compound III-8 was synthesized; mp.:102-103° C., ¹H-NMR (DMSO-d₆): δ 7.71-7.33 (series of m, 11H), 6.45 (s,1H), 6.44 (d, 1H), 5.29 (s, 1H), 3.97 (d, 1H), 3.71 (d, 1H). MS: 296.89(M+H).

EXAMPLE III-9

Synthesis of Compound III-9

Utilizing compound 31c and 3-chloromethyl-1,2,4-triazolin-5-one in step1, compound III-9 was synthesized; mp.: >300° C.; ¹H-NMR (DMSO-d₆): δ11.48 (s, 2H), 7.65-7.34 (series of m, 10H), 5.42 (s, 1H) 3.75 (d,J=13.88 Hz, 1H), 3.46 (d, J=13.91 Hz, 1H). MS: 313.93 (M+H).3-Chloromethyl-1,2,4-triazolin-5-one was described by Cowden, C. J.;Wilson R. D.; Bishop, B. C., Cottrell, I. F.; Davies, A. J.; Dolling,U-H. Tetrahedron Letters, 2000, 41, 8661. This reference has beenincorporated herein in its entirety.

EXAMPLE III-10

Synthesis of Compound III-10

Utilizing thien-2-yl-methanethiol and bromodiphenylmethane in step 1,compound III-10 was synthesized; m.p.: 122-124° C.; ¹H-NMR (DMSO-d₆): δ7.67-7.34 (series of m, 11H), 7.03 (m, 1H), 6.95 (m, 1H), 5.26 (ms, 1H),4.17 (d, 1H), 3.79 (d, 1H). MS: 312.85 (M+H),

EXAMPLE III-11

Synthesis of Compound III-11

Utilizing compound 31b and chloromethanesulfonamide in step 1, compoundIII-11 was synthesized; mp: 92-9° C., ¹H-NMR (DMSO-d₆): δ 7.57-7.26 (twosets of m, 10H), 5.59 (s, 1H), 4.27 (d, 1H), 3.90 (d, 1H). MS: 367.86(M+Na),

EXAMPLE III-12

Synthesis of Compound III-12

Utilizing compound 31b and chloroacetone in step 1, compound III-12 wasprepared; mp: 96-97° C.; ¹H-NMR (DMSO-d₆): δ 7.56-7.52 (m, 10H),7.28-7.05 (m, 4H), 5.40 (s, 1H), 3.76 (d, 1H), 3.61 (d, 1H), 2.15 (s,3H). MS: 330.95 (M+Na),

EXAMPLE III-13

Synthesis of Compound III-13

Utilizing compound 31b and 2-chloroethoxytrimethylsilane in step 1,compound III-13 was prepared; mp: 91-92° C.; ¹H-NMR (DMSO-d₆): δ7.56-7.51 (m, 4H), 7.27-7.21 (m, 4H), 5.33 (s, 1H), 4.97 (t, 1H), 3.70(m, 2H), 2.67-2.60 (m, 1H), 2.50-2.43 (m, 1H). MS: 318.96 (M+Na).

EXAMPLE III-14

Synthesis of Compound III-14

Utilizing compound 31b and 2-bromoethylmethyl ether in step 1, compoundIII-14 was prepared; mp: 83-85° C., ¹H-NMR (DMSO-d₆): δ 7.56-7.04 (2 m,8H), 5.34 (s, 1H), 3.61 (m, 2H), 3.22 (s, 3H), 2.76 (m, 1H), 2.51 (m,1H). MS: 310.91 (M+H).

EXAMPLE III-15

Synthesis of Compound III-15

Utilizing compound 31b and 1-bromo-2-(2-methoxyethoxy)ethane in step 1,compound III-15 was prepared; mp: 41-42° C.; ¹H-NMR (DMSO-d₆): δ7.56-7.22 (two m, 8H), 5.37 (s, 1H), 3.69 (m, 2H), 3.50 (m, 2H), 3.43(m, 2H), 3.31 (s, 3H), 2.76 (m, 1H), 2.50 (m, 1H). MS: 376.93 (M+Na).

-   Reagents for Step 1: TBTU/DMF/room temperature or HOBT.NH₃/EDCI-   Reagent for Step 2: 50% H₂O₂ in water/HOAc/room temperature.    Preparation of Compound 37a

The preparation of compound 37a was described in U.S. Pat. No.4,006,686, which is incorporated herein in its entirety.

EXAMPLE IV-1

Synthesis of Compound IV-1

A mixture of compound 37a (7.45 g, 27.79 mmol), O-methyl hydroxylaminehydrochloride (2.75 g, 32.93 mmol), TBTU (11.4 g, 35.5 mmol) and NMM (10mL) in dry DMF (20 mL) was stirred at room temperature overnight. Excesssolvent was removed and the mixture was diluted with EtOAc that waswashed successively with water, 2% citric acid, water, 2% NaHCO₃, waterand brine. Drying (MgSO₄) and solvent evaporation gave a crude productthat was purified by flash chromatography (silica gel, hexane:EtOAc 2:3)to generate 7.71 g of compound IV-1; ¹H-NMR (DMSO-d₆): δ 11.1 (s, 1H),7.43-7.22 (series of m, 10H), 5.43 (s, 1H), 3.55 (s, 3H), 2.86 (s, 2H).

EXAMPLE IV-2

Synthesis of Compound IV-2

Oxidation of the compound IV-1 (7.6 g, 26.48 mmol) with hydrogenperoxide (1 equiv.) in AcOH (25 mL), as described in Example III-2,generated compound IV-2 (5.98 g); mp: 140-141° C.; ¹H-NMR (DMSO-d₆): δ11.36 (s, 1H), 7.52-7.32 (series of m, 10H), 5.38 (s, 1H), 3.56 (s, 3H),3.36 (d, 1H), 3.04 (d, 1H). MS: 303.88 (M+H).

EXAMPLE IV-3

Synthesis of Compound IV-3

Utilizing compound 37a and O-Ethyl hydroxylamine hydrochloride in step1, compound IV-3 was prepared; mp: 65° C.; ¹H-NMR (DMSO-d₆): δ 11.22 (s,1H), 7.50-7.34 (series of m, 10H), 5.38 (s, 1H), 3.76 (m, 2H), 3.31 (d,1H), 3.06 (d, 1H), 1.11 (m, 3H). MS: 317.92 (M+H).

EXAMPLE IV-4

Synthesis of Compound IV-4

Utilizing compound 37b and O-methyl hydroxylamine hydrochloride in step1, compound IV-4 was prepared; mp: 103-104° C.; ¹H-NMR (DMSO-d₆): δ11.34 (s, 1H), 7.56-7.51 (m, 4H), 7.28-7.24 (m, 4H), 5.45 (s, 1H), 3.56(s, 3H), 3.40 (d, J=13.53 Hz, 1H), 2.99 (d, J=13.55 Hz, 1H). MS: 361.89(M+Na).

-   Reagents for Step 1: RMgBr or NaBH₄ (1.1-6 eqv.)/THF/0° C.-reflux.-   Reagents for Step 2: 50% H₂O₂ in water/HOAc/RT    Preparation of Compound 42b

Compound 42b was prepared as described in U.S. Pat. No. 4,006,686, whichis incorporated herein in its entirety.

EXAMPLE V-1

Synthesis of Compound V-1

Utilizing compound 42b and 2-thiophenylmagnesium bromide (1M in THF, 3.2eqv.), compound 44a was generated, which was then oxidized to givecompound V-1; mp: 130-131° C.; ¹H-NMR (DMSO-d₆): δ 8.09 (d, 1H), 8.08(d, 1H), 7.84-7.24 (series of m, 11H), 5.51 (s, 1H), 4.17 (s, 2H). MS:340.84 (M+H)

EXAMPLE V-2

Synthesis of the Compound V-2

A solution of compound 42a (the intermediate from the preparation ofcompound III-3, 6.4 g, 25 mmol) in anhydrous THF (60 mL) was addeddropwise to a solution of methyl magnesium bromide (1.4 M inTHF:toluene, 22 mL, 30.8 mmol) at 0° C. The reaction mixture was stirredat 0° C. for an additional hour, quenched with saturated ammoniumchloride solution, and extracted into EtOAc. The combined organic layerswere washed successively with water and brine, dried (MgSO₄) andconcentrated to generate compound 43a. It was then taken in HOAc (25 mL)and oxidized with hydrogen peroxide (50% in water, 1.7 mL), as describedbefore, to generate 4.31 g of compound V-2; mp: 121-122° C.; ¹H-NMR(DMSO-d₆): δ 7.53-7.30 (series of m, 10H), 5.22 (s, 1H), 4.86 (s, 1H),2.71 (d, 1H), 2.44 (d, 1H), 1.18 (s, 3H), 1.13 (s, 3H). MS: 288.96(M+H).

EXAMPLE V-3

Synthesis of Compound V-3

Utilizing compound 42b and acetylenemagnesium bromide (0.5M in THF, 6eqv) in step 1, compound V-3 was generated; ¹H-NMR (DMSO-d₆): δ7.54-7.31 (series of m, 10H), 6.99 (s, 1H), 5.32 (s, 1H), 3.69 (two s,2H), 3.15 (d, 1H), 2.74 (d, 1H). MS: 308.88 (M+H),

EXAMPLE V-4

Synthesis of Compound V-4

Utilizing compound 42c (the intermediate from Example III-12) and methylmagnesium bromide (3M in ether, 1.1 eqv), compound V-4 (foam) wasgenerated; ¹H-NMR (DMSO-d₆): δ 7.56-7.21 (two m, 8H), 5.31 (s, 1H), 4.87(s, 1H), 2.71 (d, 1H), 2.39 (d, 1H), 1.29 (s, 3H), 1.14 (s, 3H). MS:324.95 (M+H).

EXAMPLE V-5

Synthesis of the Compound V-5

To a solution of compound 42c (4.85 g, 16.60 mmol, the intermediate fromExample III-12) in methanol (85 mL) was added sodium borohydride (660mg, 17.44 mmol) in portions. The reaction mixture was then stirred atroom temperature for 0.5 h, quenched with ice-water and extracted intoEtOAc. The combined organic layers were washed with brine, dried(magnesium sulfate), and concentrated to generate compound 43d (oil,4.62 g) that was oxidized to generate compound V-5 (mixture ofdiastereomers); mp: 96-98° C., ¹H-NMR (DMSO-d₆): δ 7.56-7.21 (two m,8H), 5.38 (s, 0.72H), 5.28 (s, 0.28H), 5.05 (m, 0.28H), 4.98 (m, 0.72H),3.95 (m, 1H), 2.50 (m, 2H), 1.13 (d, 2.16H), 1.09 (d, 0.84H). MS: 310.92(M+H).

-   Reagents for Step 1: NaH/DMF/ethyl bromodifluoroacetate (compound    32)/room temperature −70° C., 4 h.-   Reagents for Step 2: Lithium aluminum hydride (“LAH”)(1M in    Et₂O)/THF/0° C., 1.5 h for compound 46; MeMgBr for compound 47.-   Reagents for Step 3: m-Chloroperbenzoic acid (“m-CPBA”),    dichloromethane, 0° C.    Preparation of Compound 31c

The preparation of compound 31c was described in U.S. Pat. No.4,066,686, which has been incorporated herein in its entirety.

Synthesis of the Compound 46

Step 1: A solution of compound 31c (9.24 g, 46.2 mmol) in dry DMF (3 mL)was slowly added to a stirred mixture of NaH (60% in oil, 2.2 g, 55mmol) in dry DMF (15 mL, room temperature, argon). The mixture wasstirred at room temperature for 15 min, treated with compound 32 (11.41g, 61 mmol) and heated at 70° C. for 4 h. The reaction mixture was thencooled to room temperature, concentrated at high vacuum, quenched withice-water and extracted into EtOAc. The combined organic layers werewashed successively with water and brine, dried (MgSO₄) and concentratedto generate compound 45 (12.34 g) that was directly used in the nextstep without any further purification.

Step 2: Thus, a solution of lithium aluminum hydride (1M in Et₂O) wasslowly added to a solution of compound 45 (6.08 g, 18.88 mmol) in dryTHF (50 mL, 0° C., argon). The mixture was stirred at 0° C. for 1.5 h,treated successively (carefully) with EtOAc (5 mL), water (5 mL), and10% H₂SO₄ (20 mL). The mixture was then extracted into EtOAc. Thecombined organic layers were washed successively with water (twice) andbrine, dried (MgSO₄), and concentrated to give a crude product that waspurified by flash chromatography (silica gel, hexane:EtOAc 4:1) togenerate compound 46 (syrup, 2.87 g); ¹H-NMR (DMSO-d₆): δ 7.47-7.22 (3m, 10H), 5.86 (t, 1H), 5.78 (s, 1H), 3.70 (m, 2H).

EXAMPLE VI-1

Synthesis of Compound VI-1

Following the procedure as described in Example 11-19, compound 46 (2.68g, 9.57 mmol) was oxidized with m-CPBA (77%, 2.36 g, 10.53 mmol) togenerate compound VI-1 (2.08 g), mp: 77-79° C., ¹H-NMR (DMSO-d₆): δ7.58-7.32 (two m, 10H), 6.05 (m, 1H), 5.68 (s, 1H), 3.99-3.70 (two m,2H). MS: 318.96 (M+H).

EXAMPLE VI-2

Synthesis of Compound VI-2

Step 2: A solution of compound 45 (5.7 g, 17.7 mmol) in dry THF (40 mL)was added dropwise to a solution of methyl magnesium bromide (1.4 M intoluene, 65 mL, 91 mmol) under argon at room temperature. The reactionmixture was then stirred for 6 h, quenched with saturated ammoniumchloride solution, and extracted into EtOAc. The combined organic layerswere washed successively with water and brine, dried (MgSO₄) andconcentrated to give a crude product that was purified by flashchromatography (silica gel, hexane: EtOAc 1:1) to provide compound 47(766 mg) that was utilized in the next step; ¹H-NMR (DMSO-d₆): δ7.55-7.26 (series of m, 10H), 5.6 (s, 1H), 4.84 (s, 1H), 1.19 (twooverlapping s, 6H), 1.09 (s, 3H), 0.9 (s, 3H).

Step 3: Thus, oxidation of compound 47 (0.76 g, 2.53 mmol) with m-CPBA(77%, 0.625 g, 2.78 mmol), following the procedure described in ExampleIII-2, generated compound VI-2 (0.291 g); mp: 103-104° C.; ¹H-NMR(DMSO-d₆): δ 7.55-7.24 (two m, 10H), 5.60 (s, 1H), 4.84 (s, 1H), 1.19(s, 6H), 1.09 (s, 3H), 0.90 (s, 3H). MS: 316.95 (M+H).

-   Reagents for Step 1: NaH/DMF/room temperature.-   Reagents for Step 2: 1N NaOH/EtOH/reflux.-   Reagents for Step 3: HOBT.NH₃/EDCI/DMF/room temperature.-   Reagents for Step 4: 50% H₂O₂ in water/HOAc/room temperature.

EXAMPLE VII-1

Synthesis of Compound VII-1

A solution of compound 31c (8.89 g, 44.45 mmol) in dry DMF (20 mL) wasadded dropwise to a stirred mixture of NaH (60% in oil, 2.2 g, 55 mmol)in dry DMF (40 mL, under argon, room temperature). The mixture wasstirred for 15 min, treated with compound 53 (8 mL, 50.3 mmol) andstirred overnight. Excess solvent was removed and the residue wasquenched with water followed by extraction into EtOAc. The combinedorganic layers were washed successively with water (twice) and brine,dried (MgSO₄) and concentrated to give a residue that was purified byflash chromatography (silica gel, hexane:EtOAc 3:2) to generate compoundVII-1 (oil, 6.68 g); ¹H-NMR (DMSO-d₆): δ 7.44-7.20 (m, 10H), 5.21 (m,10H), 5.21 (s, 1H), 3.6 (s, 3H), 2.7 (m, 1H), 2.16 (m, 1H), 1.98-1.15(series of m, 8H).

EXAMPLE VII-2

Synthesis of Compound VII-2

A mixture of the compound VII-1 (6.68 g, 19.64 mmol), NaOH (1N, 100 mL)and EtOH (100 mL) was kept under reflux for 3 h. The mixture was cooledto room temperature, concentrated and washed with ether. The basicaqueous layer was neutralized with conc. HCl and extracted into EtOAc.The combined organic layers were washed successively with water (twice)and brine, dried (MgSO₄), and concentrated to yield compound 55 that wasdirectly used in the next step without further purification.

Thus, a mixture of compound 55 (4.96 g, 15.21 mmol), HOBT.NH₃ complex (5g, 32.89 mmol followed by an additional amount of 2.5 g, 16.44 mmolafter 2 h), EDCI (3.5 g, 18.3 mmol followed by an additional amount of1.75 g, 9.1 mmol after 3 h) in DMF (50 mL) was stirred at roomtemperature overnight, diluted with dichloromethane, washed successivelywith water, 2% citric acid, water, 2% NaHCO₃, water and brine, and dried(MgSO₄). Solvent evaporation generated a crude product that was purifiedby flash chromatography (silica gel, hexane:EtOAc::1:2) to yieldcompound VII-2 (2.42 g); ¹H-NMR (DMSO-d₆): δ 7.44-7.06 (series of m,10H), 6.98 (br s, 2H), 5.30 (s, 1H), 3.03 (m, 1H), 2.43 (m, 1H),1.83-1.11 (series of m, 8H).

EXAMPLE VII-3

Synthesis of Compound VII-3

To a solution of the compound VII-2 (2.2 g, 6.76 mmol) in AcOH (10 mL)was added hydrogen peroxide (50% solution in water, 470 μL). Thereaction mixture was stirred at room temperature for 5 h, filtered andconcentrated to give a crude product that was purified by flashchromatography (silica, EtOAc) to generate compound VII-3 (0.593 g) mp:155-156° C., ¹H-NMR (DMSO-d₆): δ 7.55-7.30 (series of m, 11H), 7.07 (s,1H), 5.14 (s, 1H), 2.73 (m, 1H), 2.63 (m, 1H), 1.82-1.19 (series of m,8H). MS: 342 (M+Na).

-   Reagents for Step 1: a) 100° C.; b): HOBT.NH₃/TBTU/DMF/room    temperature.-   Reagents for Step 2: 50% H₂O₂ in water/HOAc/0° C. to room    temperature.    Preparation of Compound 57

The preparation of compound 57 was described by Seebach, D.; Teschner,M. Chem. Ber. 1976, 109, 1601, which is incorporated herein in itsentirety.

EXAMPLE VIII-1

Synthesis of Compound VIII-1

A mixture of compound 57 (116 mg, 0.79 mmol and 304 mg, 2.08 mmol,respectively, in two batches) and compound 58 (1 eqv. in each case) washeated at 100° C. for 1 h and cooled to room temperature to give anadduct that was subjected to subsequent amidation as described in SchemeVII, Step 3, to generate compound VIII-1 (0.346 g from two batches);¹H-NMR (DMSO-d₆): δ 7.49-7.27 (series of m, 11H), 7.04 (s, 1H), 5.23 (s,1H), 2.02-1.35 (3 m, 8H).

EXAMPLE VII-2

Synthesis of the Compound VIII-2

Following the procedure described in Example III-2, compound VIII-1 (342mg, 1.09 mmol) was oxidized with hydrogen peroxide (75 μL) in AcOH (5mL) to generate compound VIII-2 (0.282 g); mp: 129-130° C.; ¹H-NMR(DMSO-d₆): 7.47-7.28 (m, 11H), 7.15 (s, 1H), 5.13 (s, 1H), 1.93-1.26 (3m, 8H). MS: 328 (M+H)

-   Reagents for Step 1: a) 10 N NaOH/EtOH/70° C.; b) compound 57, 70°    C., overnight.-   Reagents for Step 2: HOBT.NH₃/TBTU/NMM/DMF/room temperature.-   Reagents for Step 3: 50% H₂O₂ in water/HOAc/room temperature.

EXAMPLE IX-1

Synthesis of the Compound IX-1

A mixture of compound 31a (2 g, 6.19 mmol), 10N NaOH (3 mL, 30 mmol) andwater (3 mL) was stirred under argon at 70° C. for 15 min, treated withcompound 57 (1 mL, 6.17 mmol) followed by heating at 70° C. overnight,and cooled to room temperature. It was then extracted into ether and thecombined organic layers were washed successively with water and brine,dried (MgSO₄) and concentrated to generate compound 58a (1.46 g) thatwas directly taken to next step without further purifications. Thus, amixture of compound 58a (1.45 g, 4.8 mmol), HOBT.NH₃ complex (1.63 g,10.72 mmol), TBTU (1.87 g, 5.8 mmol), and NMM (2 mL) in dry DMF (10 mL)was stirred at room temperature overnight, diluted with EtOAc and washedsuccessively with water, 2% citric acid, water, 2% NaHCO₃, water andbrine. Drying (MgSO₄) and solvent evaporation generated a crude productthat was purified by flash chromatography (silica gel, hexane: EtOAc3:7) to yield compound IX-1 (0.395 g); ¹H-NMR (DMSO-d₆): δ 7.42-7.20 (3m, 10H), 6.97 (two overlapping broad s, 2H), 5.37 (s, 1H), 2.62 (s, 2H),0.97 (m, 2H), 0.53 (m, 2H).

EXAMPLE IX-2

Synthesis of Compound IX-2

Following the procedure described in Example III-2, compound IX-1 (384mg, 1.29 mmol) was oxidized with hydrogen peroxide (90 μL) in AcOH (3mL) to generate compound IX-2 (0.342 g); mp 158-159° C.; ¹H-NMR(DMSO-d₆): δ 7.5-7.3 (m, 10H), 6.9 (two broad overlapping s, 2H), 5.23(s, 1H), 3.13 (d, 1H), 2.31 (d, 1H), 1.23-0.62 (4 m, 4H). MS: 336(M+Na).

EXAMPLE IX-3

Synthesis of Compound IX-3

Utilizing compound 31b and compound 57 in step 1 and following theprocedure as described above, compound IX-3 was generated; mp: 162° C.;¹H-NMR (DMSO-d₆): δ 7.54-7.50 (m, 4H), 7.26-7.21 (m, 4H), 6.97 (twooverlapping broad s, 2H), 5.32 (s, 1H), 3.2 (d, 1H), 2.19 (d, 1H),1.20-0.69 (4 m, 4H). MS: 350 (M+H)

-   Reagents in Step 1: a) K₂CO₃/toluene/room temperature to 80° C. b)-   K₂CO₃/Bu₄NHSO₄/Toluene/80° C.-   Reagents in Step 2: 1N NaOH/MeOH/reflux.-   Reagents in Step 3: HOBT.NH₃/EDCI/DMF/RT.-   Reagents in Step 4: 50% H₂O₂ in water/HOAc/room temperature.    Preparation of Compound 59

Preparation of compound 59 was described by Hoffmann, H. M. R.; Eggert,U.; Walenta, A.; Weineck, E.; Schomburg, D.; Wartchow, R.; Allen, F. H.J. Org. Chem. 1989, 54, 6096, which is incorporated herein by referencein its entirety.

Preparation of Compound 60

A mixture of the compound 31c (3.66 g, 18.3 mmol), compound 59 (6.3 g,24.23 mmol), anhydrous K₂CO₃ (7.5 g, 54.34 mmol) in anhydrous toluene(50 mL) was stirred at room temperature for 96 h and then at 80° C. for3 h. n-Bu₄NHSO₄ (450 mg) was added to the reaction mixture and stirringwas continued at 80° C. for another 72 h. Additional quantities of K₂CO₃(3 g), Bu₄NHSO₄ (150 mg), and toluene (20 mL) were then added to thereaction mixture and heating (at 80° C.) was continued for another 96 h.After cooling to room temperature, the reaction mixture was filtered andresidue was washed with diethyl ether. The combined filtrate andwashings were concentrated to give the crude product, 60, (5.17 g) whichwas directly used for the next step without further purifications.

Preparation of Compound 62

A mixture of compound 60 (5.15 g, 17.28 mmol), NaOH (1N, 100 mL),methanol (100 mL) was kept under reflux for 4 h, cooled to roomtemperature, and concentrated to remove excess methanol. Basic layer wasacidified with conc. HCl and extracted into EtOAc. The combined organiclayers were washed with brine, dried (MgSO₄), and concentrated togenerate compound 61 (4.45 g) that was directly used in the next step.

Thus, a mixture of compound 61 (4.43 g, 15.65 mmol), HOBT.NH₃ complex(5.3 g, 34.86 mmol), EDCI (3.5 g, 18.3 mmol), DMAP (380 mg) in DMF (30mL) was stirred at room temperature overnight, diluted withdichloromethane, successively washed successively with water, 2% citricacid, water, 2% NaHCO₃, water and brine, and dried (MgSO₄). Solventevaporation gave a crude product that was purified by flashchromatography (silica gel, hexane:EtOAc 1:1) to generate the product(2.38 g); ¹H-NMR (DMSO-d₆): δ 7.45-7.21 (3 m, 12H), 5.37 (s, 1H), 1.76(m, 2H), 0.82 (m, 2H).

EXAMPLE X-1

Synthesis of Compound X-1

Compound 62 (2.34 g, 8.26 mmol) was oxidized with hydrogen peroxide (570μL) in AcOH (12 mL) to generate compound X-1 (1.81 g); mp: 148-149° C.,¹H-NMR (DMSO-d₆): 67.5-7.31 (m, 11H), 7.25 (s, 1H), 5.51 (s, 1H), 1.0(m, 2H), 0.63 (m, 2H). MS: 322 (M+Na).

Utility

The present invention provides a method of treating diseases andconditions in a subject in need thereof comprising administering to saidsubject a therapeutically effective amount of a compound of the presentinvention. For example, the compounds of the present invention may beuseful for the treatment of diseases, such as excessive sleepiness,promotion and/or improvement of wakefulness (preferably improvement ofwakefulness in patients with excessive sleepiness associated withnarcolepsy, sleep apnea (preferably obstructive sleep apnea/hypopnea)and shift work disorder), treatment of Parkinson's disease, Alzheimer'sdisease, cerebral ischemia, stroke, eating disorders, attention deficitdisorder (“ADD”), attention deficit hyperactivity disorder (“ADHD”),depression, schizophrenia, fatigue (preferably fatigue associated withcancer or neurological diseases, such as multiple sclerosis and chronicfatigue syndrome), stimulation of appetite and weight gain andimprovement of cognitive dysfunction.

Methodology: Evaluation of Wake Promoting Activity in Rats

The methodology utilized for evaluating wake promoting activity of testcompounds is based on that described by Edgar and Seidel, Journal ofPharmacology and Experimental Therapeutics, 283:757-769, 1997, andincorporated herein in its entirety by reference.

Animal Surgery. Adult, male Wistar rats (275-320 g from Charles RiverLaboratories, Wilmington, Mass.) were anesthetized (Nembutal, 45 mg/kg,ip.) and surgically prepared with implants for recording of chronic EEG(encephalographic) and EEG (electromyographic) recording. The EEGimplants were made from commercially available components (Plastics One,Roanoke, Va.). EEG signals were recorded from stainless steel screwelectrodes: 2 frontal (+3.0 mm AP from bregma, ±2.0 mm ML), and 2occipital (−4.0 mm AP from bregma, ±2.0 mm ML). Two Teflon-coatedstainless steel wires were positioned under the nuchal trapezoid musclesfor EEG recording. All electrode leads were inserted into a connectorpedestal and the pedestal affixed to the skull by application dentalacrylic. Antibiotic was administered post surgically and antibioticcream was applied to the wound edges to prevent infection. At least oneweek elapsed between surgery and recording.

Recording environment. Postsurgically, rats were housed in pairs in anisolated room. Food and water were available ad libitum, ambienttemperature was 21° C., and humidity was 55%. At least 24 hrs prior torecording, they were placed in Nalgene containers (31×31×31 cm) with awire-grid top, and entry to the room was prohibited during the day ofrecording except for dosing. The containers were placed on a rack withtwo shelves, 4 containers per shelf. Fluorescent overhead room lightswere set to a 24 hr. light/dark cycle (on at 7 AM, off at 7 PM). Lightlevels inside the containers were 38 and 25 lux for the top and bottomshelves respectively. Background white-noise (68 db inside thecontainers) was present in the room to mask ambient sounds.

Data acquisition. EEG and EEG signals were led via cables to acommutator (Plastics One) and then to pre-amplifiers (model 1700, A-MSystems, Carlsborg, Wash.). EEG and EMG signals were amplified (10K and1K respectively) and band pass filtered between 0.3 and 500 Hz for EEGand between 10 and 500 Hz for EMG. These signals were digitized at 128samples per second using ICELUS sleep research software (M. Opp, U.Texas; see Opp, Physiology and Behavior 63:67-74, 1998, and Imeri,Mancia, and Opp, Neuroscience 92:745-749, 1999, incorporated byreference herein in their entirety) running under Labview 5.1 softwareand data acquisition hardware (PCI-MIO-16E-4; National Instruments,Austin, Tex.). On the day of dosing, data was recorded for 6 to 10 hoursbeginning at 11 AM.

Drug administration and study design. Compounds were evaluated on groupsof from 4 to 8 rats carried out over one or two separate test sessions.Each animal was tested with a different compound or vehicle for up to 10weeks with at least 7 days between successive tests. A vehicle group wasincluded in all experiments, and each animal received vehicle every4^(th) test. Test compounds were suspended in sterile 0.25%methylcellulose (pH=6.2; Upjohn Co., Kalamazoo, Mich.) at 30 mg/mL.Unless otherwise noted, compounds were administered at a single dose of100 mg/kg. Dosing was carried out at noon, while the rats werepredominantly asleep. Each rat was lifted out of its container, given anintraperitoneal injection in a volume of 5 mL/kg, and replaced. Dosingrequired approximately 30 sec per rat.

Sleep/wake scoring. Sleep and wake activity were determined using aprocedure involving manual scoring using the ICELUS software, followedby application of an autoscoring program written in Microsoft Excel(Microsoft, Inc., Redmond, Wash.) The ICELUS program displays the EEGand EMG data in blocks of 6 sec along with the EEG frequency spectrum(FFT) amplitudes. Arousal state was scored as awake, rapid eye-movement(REM), or slow-wave or non-REM sleep according to visual analysis of EEGfrequency and amplitude characteristics and EMG activity (Opp andKrueger, 1994; Van Gelder, et al., 1991; Edgar, et al., 1991, 1997;Seidel, et al, 1995, incorporated by reference herein in theirentirety). Essentially, waking activity consists of relativelylow-amplitude EEG activity with relatively lower power in the frequencyband from 0.5-6 Hz, accompanied by moderate to high level EMG activity.In a particular waking state (“theta-waking”), EEG power can berelatively focused in the 6-9 Hz (theta) range, but significant EMGactivity is always present. NREM sleep is characterized by relativehigh-amplitude EEG activity with relatively greater power in the lowfrequency band from 0.5-6 Hz, accompanied by little or no EMG activity.REM sleep is characterized by moderate and constant amplitude EEGfocused in the theta (6-9 Hz) range, similar to waking theta, but withno EMG activity.

To convert the raw data to sleep/wake stage scores, normally the firsthour of activity (prior to dosing) is manually scored into sleep, wake,or REM states. Subsequent activity is evaluated using a computeralgorithm which takes into account FFT amplitudes, theta-band activity,and EMG activity for each 6 second epoch. An iterative procedure is usedto adjust 3 different parameter thresholds until the first hour of datascored by the computer algorithm matches as closely as possible with themanual values. These parameter values are then used to score theremaining activity. The data are then reduced to “wake” (wake+wakingtheta activity) or “sleep” (REM+non-REM) for each 6 sec epoch. The timespent awake was then calculated for each 5 and 30 min interval relativeto the specific time of dosing (approximately 12:00 noon).

Data Analysis and Statistics.

Two basic outcome measures were used to ascertain whether a compoundexhibited wake-enhancing activity. The first was the percent time spentawake (0-100%) for each 30 min period following dosing. The second wasthe sum in minutes of the time spent awake for the first 6 half-hourperiods following dosing (3 hr AUC; maximum 180 min).

For purposes of ascertaining activity of a test compound, wake activityvalues were compared against corresponding vehicle values. The vehiclevalues were of two types. The first type was the correspondingwithin-experiment vehicle, that is, a value derived from the vehiclegroup run concurrently with the test compound. A second referencevehicle value was also used for comparison, which consisted of the mean3 hr AUC value calculated from 234 animals in 59 separate experimentscarried out during the same time period as the evaluations of the testcompounds (mean±SD=69.22±20.12; 95% confidence limits=66.63-71.81).Two-tailed, unpaired t-tests were performed on the wake time values fordrug versus vehicle treated animals, and compounds with p≦0.05 weredeemed significantly wake-promoting. A test compound was consideredactive as a wake promoting agent if it met one or more of the followingthree criteria.

-   -   (i) The 3 hr AUC value for the test compound was significantly        greater (p≦0.05) than the mean wake value for the reference        vehicle group (N=234).    -   (ii) The 3 hr AUC value for the test compound was significantly        greater (p≦0.05) than the corresponding value for the within        -experiment vehicle group.    -   (iii) One or more of the half-hour wake time values from 0.5 to        2 hrs after dosing were significantly greater (p≦0.05) in the        test compound group compared to the within-experiment vehicle        group.

Results.

Compounds of the invention either have demonstrated or are expected todemonstrate utility for wake promoting activity.

References. The following references, to the extent that they provideexemplary procedural or other details supplementary to those set forthherein, are specifically incorporated in their entirety herein byreference:

-   Touret, et al., Neuroscience Letters, 189:43-46, 1995.-   Van Gelder, R. N. et al., Sleep 14:48-55, 1991.-   Edgar, D. M., J. Pharmacol. Exp. Ther. 282:420-429, 1997.-   Edgar and Seidel, J. Pharmacol. Exp. Ther., 283:757-69, 1997.-   Hernant et al., Psychopharmacology, 103:28-32, 1991.-   Lin et al., Brain Research, 591:319-326, 1992.-   Opp and Krueger, American Journal of Physiology 266:R688-95, 1994-   Panckeri et al., Sleep, 19(8):626-631, 1996.-   Seidel, W. F., et al., J. Pharmacol. Exp. Ther. 275:263-273, 1995.-   Shelton et al., Sleep 18(10):817-826, 1995.-   Welsh, D. K., et al., Physiol. Behav. 35:533-538, 1985.    Dosage and Formulation.

The compounds of the present invention can be administered fortherapeutic purposes by any means that results in the contact of theactive agent with the agent's site of action in a subject. The compoundsmay be administered by any conventional means available for use inconjunction with pharmaceuticals, either as individual therapeuticagents or in a combination with other therapeutic agents, such as, forexample, analgesics, or in combination with antidepressants, includingbut are not limited to tricyclic antidepressants (“TCAs”), SelectiveSerotonin Reuptake Inhibitors (“SSRI”), Serotonin and NoradrenalinReuptake Inhibitors (“SNRIs”), Dopamine Reuptake Inhibitors (“DRIs”),Noradrenalin Reuptake Inhibitors (“NRUs”), Dopamine, Serotonin andNoradrenalin Reuptake Inhibitors (“DSNRIs”) and Monoamine OxidaseInhibitors (“MAOIs) including reversible inhibitors of monoamine oxidasetype A (RIMAs). The compounds of the present invention are preferablyadministered in therapeutically effective amounts for the treatment ofthe diseases and disorders described herein.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques. The effective dose will vary depending upon anumber of factors, including the pharmacodynamics of the active agent,the type and extent of progression of the disease or disorder, the age,weight and health of the particular patient, the formulation of theactive and its mode and frequency of administration, and the desiredeffect with a minimization of side effects. Typically, the compounds areadministered at lower dosage levels, with a gradual increase until thedesired effect is achieved.

Typical dose ranges are from about 0.01 mg/kg to about 100 mg/kg of bodyweight per day, with a preferred dose from about 0.01 mg/kg to 10 mg/kgof body weight per day. A typical daily dose for adult humans can rangefrom about 1 to about 1000 mg of the active agent, particularly fromabout 1 to about 400 mg, and including 25, 50, 85, 100, 150, 170, 200,255, 250, 255, 340, 400, 425, 500, 600, 700, 750, 800, and 900 mg doses,and equivalent doses for a human child.

The compounds may be administered in one or more unit dose forms, andthey may be administered in a single daily dose or in two, three or fourdoses per day. The unit dose ranges from about 1 to about 1000 mg,particularly from about 1 to about 400 mg, and including 25, 50, 85,100, 150, 170, 200, 255, 250, 255, 340, 400, 425, 500, 600, 700, 750,800, and 900 mg unit doses, and equivalent unit doses for a human child.In particular, the unit dosages range from about 1 to about 500 mgadministered one to four times a day, preferably from about 10 mg toabout 300 mg, two times a day. In an alternate method of describing aneffective dose, an oral unit dose is one that is necessary to achieve ablood serum level of about 0.05 to 20 μg/ml in a subject, and preferablyabout 1 to 20 μg/ml.

The compounds of the present invention may be formulated intopharmaceutical compositions by admixture with one or morepharmaceutically acceptable excipients. The active agent may be presentin about 0.5-95% by weight of the composition. The excipients areselected on the basis of the chosen route of administration and standardpharmaceutical practice, as described, for example, in Remington: TheScience and Practice of Pharmacy, 20^(th) ed.; Gennaro, A. R., Ed.;Lippincott Williams & Wilkins: Philadelphia, Pa., 2000.

The compositions can be prepared for administration by oral means,including tablets, pills, powders, capsules, troches and the like;parenteral means, including intravenous, intramuscular, and subcutaneousmeans; topical or transdermal means, including patches, creams,ointments, lotions, pastes, gels, solutions, suspensions, aerosols, andpowders and the like; transmucosal means, including nasal, rectal,vaginal, sublingual and buccal means; ophthalmic or inhalation means.Preferably the compositions are prepared for oral administration,particularly in the form of tablets, capsules or syrups; parenteraladministration, particularly in the form of liquid solutions,suspensions or emulsions; intranasal administration, particularly in theform of powders, nasal drops, or aerosols; or for topical use, such aspatches, creams, ointments, and lotions.

For oral administration, the tablets, pills, powders, capsules, trochesand the like can contain one or more of the following: diluents orfillers such as starch, or cellulose; binders such as microcrystallinecellulose, gelatins, or polyvinylpyrrolidone; disintegrants such asstarch or cellulose derivatives; lubricants such as talc or magnesiumstearate; glidants such as colloidal silicon dioxide; sweetening agentssuch as sucrose or saccharin; and flavoring agents such as peppermint orcherry flavoring. Capsules may contain any of the above ingredients, andmay also contain a semi-solid or liquid carrier, such as a polyethyleneglycol. The solid oral dosage forms may have coatings of sugar, shellac,or enteric agents. Liquid preparations may be in the form of aqueous oroily suspensions, solutions, emulsions, syrups, elixirs, etc., or may beprovided as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as surfactants, suspending agents,emulsifying agents, diluents, sweetening and flavoring agents, dyes andpreservatives.

The compositions may also be administered parenterally. Thepharmaceutical forms acceptable for injectable use include, for example,sterile aqueous solutions, or suspensions. Aqueous carriers includemixtures of alcohols and water, buffered media, and the like. Nonaqueoussolvents include alcohols and glycols, such as ethanol, and polyethyleneglycols; oils, such as vegetable oils; fatty acids and fatty acidesters, and the like. Other components can be added includingsurfactants; such as hydroxypropylcellulose; isotonic agents, such assodium chloride; fluid and nutrient replenishers; electrolytereplenishers; agents which control the release of the active compounds,such as aluminum monostearate, and various co-polymers; antibacterialagents, such as chlorobutanol, or phenol; buffers; suspending agents;thickening agents; and the like. The parenteral preparations can beenclosed in ampules, disposable syringes or multiple dose vials. Otherpotentially useful parenteral delivery systems for the active compoundsinclude ethylene-vinyl acetate copolymer particles, osmotic pumps,implantable infusion systems, and liposomes.

Other possible modes of administration include formulations forinhalation, which include such means as dry powder, aerosol, or drops.They may be aqueous solutions containing, for example,polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oilysolutions for administration in the form of nasal drops, or as a gel tobe applied intranasally. Formulations for topical use are in the form ofan ointment, cream, or gel. Typically these forms include a carrier,such as petrolatum, lanolin, stearyl alcohol, polyethylene glycols, ortheir combinations, and either an emulsifying agent, such as sodiumlauryl sulfate, or a gelling agent, such as tragacanth. Formulationssuitable for transdermal administration can be provided as discretepatches, as in a reservoir or microreservoir system, adhesivediffusion-controlled system or a matrix dispersion-type system.Formulations for buccal administration include, for example lozenges orpastilles and may also include a flavored base, such as sucrose oracacia, and other excipients such as glycocholate. Formulations suitablefor rectal administration are preferably provided as unit-dosesuppositories, with a solid based carrier, such as cocoa butter, and mayinclude a salicylate.

The compositions of the present invention may be formulated to controland/or delay the release of the active agent(s). Such controlled-,delayed-, sustained-, or extended-release compositions are well-known inthe art, and may include, for example, reservoir or matrix diffusionproducts, as well as dissolution systems. Some compositions may utilize,for example biocompatible, biodegradable lactide polymer,lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylenecopolymers as excipients.

As those skilled in the art will appreciate, numerous modifications andvariations of the present invention are possible in light of the aboveteachings. It is therefore understood that within the scope of theappended claims, the invention may be practiced otherwise than asspecifically described herein, and the scope of the invention isintended to encompass all such variations.

1. A compound of formula (I):

wherein rings A and B, together with the carbon atoms to which they areattached, are each independently selected from: a) a 6-membered aromaticcarbocyclic ring in which from 1 to 3 carbon atoms may be replaced byhetero atoms selected from oxygen, nitrogen and sulfur; and b) a5-membered aromatic carbocyclic ring in which either: i) one carbon atommay be replaced with an oxygen, nitrogen, or sulfur atom; ii) two carbonatoms may be replaced with a sulfur and a nitrogen atom, an oxygen and anitrogen atom, or two nitrogen atoms; or iii) three carbon atoms may bereplaced with three nitrogen atoms, one oxygen and two nitrogen atoms,or one sulfur and two nitrogen atoms; wherein said rings are optionallysubstituted with one to three R²⁰ groups; X is not present, is a bond,O, S(O)_(y), NR¹⁰, C₂ alkylene, C₂₋₃ alkenylene, C(═O), C(R²¹)₂NR¹⁰,C(R²¹)═N, N═C(R²¹), C(═O)N(R¹⁰), or NR¹⁰C(═O); wherein said alkylene andalkenylene groups are optionally substituted with one to three R²⁰groups; R is H or C₁-C₆ alkyl; Y is selected from: a) C₁-C₆alkylene-R¹;b) C₁-C₆ alkylene-R²; c) (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n)—R¹;d) C₁-C₆ alkylene-O(CH₂)_(p)OR²¹, e) C₁-C₆ alkyl substituted with one ortwo OR²¹ groups; provided that Y cannot be (CH₂)₁₋₄OR²¹; and f)CH₂CR²¹═C(R²¹)₂ except when X is a bond and q is 2; wherein said alkyland alkylene groups are optionally substituted with one to three R²⁰groups; Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C═C(R²¹)₂, C≡C, C₆-C₁₀arylene, 5-10 membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6membered heterocycloalkylene; wherein said arylene, heteroarylene,cycloalkylene, and heterocycloalkylene groups are optionally substitutedwith one to three R²⁰ groups; R¹ is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴,C(═O)R¹⁵, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴,C(═NR¹¹)NR¹²R¹³, NR²¹S(O)₂R”, S(O)₂NR¹²R¹³, NR²¹S(O)₂NR¹²R¹³, andPO(OR²¹)₂; R² is a 5-6 membered heteroaryl, wherein said heteroarylgroup is optionally substituted with one to three R²⁰ groups; R¹⁰ andR^(10A) at each occurrence are independently selected from H, C₁-C₆alkyl, C₆-C₁₀ aryl, C(═O)R¹⁵, and S(O)_(y)R¹⁴; wherein said alkyl andaryl groups are optionally substituted with one to three R²⁰ groups; R¹¹at each occurrence is independently selected from H and C₁-C₆ alkyl;wherein said alkyl is optionally substituted with one to three R²⁰groups; R¹² and R¹³ at each occurrence are each independently selectedfrom H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together with thenitrogen to which they are attached, form a 3-7 memberedheterocycloalkyl ring; wherein said alkyl and aryl groups andheterocycloalkyl ring are optionally substituted with one to three R²⁰groups; R¹⁴ at each occurrence is independently selected from C₁-C₆alkyl, C₆-C₁₀ aryl, and arylalkyl; wherein said alkyl, aryl andarylalkyl groups are optionally substituted with one to three R²⁰groups; R¹⁵ at each occurrence is independently selected from C₁-C₆alkyl, C₆-C₁₀ aryl, arylalkyl, and heteroaryl; wherein said alkyl, aryl,arylalkyl, and heteroaryl groups are optionally substituted with one tothree R²⁰ groups; R²⁰ at each occurrence is independently selected fromF, Cl, Br, I, OR²¹, OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl,C₃-C₆ spirocycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,arylalkyl, ═O, C(═O)R²², CO₂R²¹, OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²²,NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹C(═S)R²², and S(O)_(y)R²²;R²¹ at each occurrence is independently selected from H and C₁-C₆ alkyl;R²² at each occurrence is independently selected from C₁-C₆ alkyl, andC₆-C₁₀ aryl; R²³ and R²⁴ at each occurrence are each independentlyselected from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, togetherwith the nitrogen to which they are attached, form a 3-7 memberedheterocycloalkyl ring; R²⁵ at each occurrence is independently theresidue of an amino acid after the hydroxyl group of the carboxyl groupis removed; m is 0 or 1; n is 0 or 1; p is 1, 2, 3, or 4; q is 0, 1, or2; y is 0, 1, or 2; with the following provisos: 1) when R=H, Y is(C₁-C₆ alkylene)-R¹, and R¹ is CO₂R¹¹ or C(═O)NR¹²R¹³, then the alkylenegroup must be substituted with a spirocycloalkyl group; 2) when X is notpresent, then R¹ cannot be NR¹²R¹³; and the stereoisomeric forms,mixtures of stereoisomeric forms or pharmaceutically acceptable saltsforms thereof.
 2. The compound of claim 1 wherein q is
 1. 3. Thecompound of claim 1 wherein X is not present.
 4. The compound of claim 1wherein X is a bond, O, C₂ alkylene, or C(═O).
 5. The compound of claim4 wherein X is a bond.
 6. The compound of claim 1 wherein rings A and B,together with the carbon atoms to which they are attached, are eachindependently selected from: a) a 6-membered aromatic carbocyclic ringin which from 1 to 3 carbon atoms may be replaced by nitrogen atoms; andb) a 5-membered aromatic carbocyclic ring in which either: i) one carbonatom may be replaced with an oxygen, nitrogen, or sulfur atom; ii) twocarbon atoms may be replaced with a sulfur and a nitrogen atom, anoxygen and a nitrogen atom, or two nitrogen atoms.
 7. The compound ofclaim 6 wherein rings A and B are each independently selected fromphenylene, pyridylene, pyrazinylene, pyrimidinylene, pyrrolylene,pyrazolylene, imidazolylene, furylene, and thienylene.
 8. The compoundof claim 1 wherein R is H.
 9. The compound of claim 1 wherein R is C₁-C₄alkyl.
 10. The compound of claim 1 wherein Y is C₁-C₆ alkylene-R¹; or(C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n)-R¹; wherein said alkylenegroups are optionally substituted with one to three R²⁰ groups.
 11. Thecompound of claim 10 wherein Y is C₁-C₆ alkylene-R¹.
 12. The compound ofclaim 11 wherein Y is CH₂—R¹.
 13. The compound of claim 10 wherein Y is(C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n)-R¹.
 14. The compound ofclaim 1 wherein Y is C₁-C₆ alkylene-R².
 15. The compound of claim 1wherein Y is C₁-C₆ alkylene-O(CH₂)_(p)OR²¹.
 16. The compound of claim 1wherein Y is C₁-C₆ alkyl substituted with one or two OR²¹ groups. 17.The compound of claim 1 wherein Y is CH₂CR²¹═C(R²¹)₂.
 18. The compoundof claim 1 wherein R¹ is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁵,C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴, NR²¹S(O)₂R¹¹, S(O)₂NR¹²R¹³, and PO(OR²¹)₂.19. The compound of claim 18 wherein R¹ is selected from NR¹²R¹³,NR²¹C(═O)R¹⁴, C(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, and S(O)₂NR¹²R¹³.
 20. Thecompound of claim 19 wherein R¹ is NR²¹C(═O)R¹⁴, C(═O)NR¹²R¹³,NR²¹S(O)₂R¹¹, or S(O)₂NR¹²R¹³.
 21. The compound of claim 20 wherein R¹is C(═O)NR¹²R¹³.
 22. A compound of formula (III):

wherein rings A and B, together with the carbon atoms to which they areattached, are each independently selected from phenylene, pyridylene,furylene, thienylene, or a 5-membered aromatic ring in which 1-3 carbonatoms may be replaced with a nitrogen atom; wherein said rings areoptionally substituted with one to three R²⁰ groups; X is not present,is a bond, O, S(O)_(y), or NR¹⁰, wherein said alkylene and alkenylenegroups are optionally substituted with one to three R²⁰ groups; R is Hor C₁-C₄ alkyl; Y is selected from: a) C₁-C₆ alkylene-R¹; b) C₁-C₆alkylene-R²; c) (C₁-C₄ alkylene)_(m)-Z¹-(C₁-C₄ alkylene)_(n)-R¹, orC₁-C₄ alkylene-Z²-C₁-C₄ alkylene-R¹; d) C₁-C₆ alkylene-O(CH₂)_(p)OR²¹,e) CH₂C(OH)(CH₃)₂, CH₂C(CH₃)₂OH, CH₂C(OH)₂CF₃, CH₂C(OH)(C≡CH)₂, orCH₂CH(OH)CH₃, and f) CH₂CR²¹═C(R²¹)₂, or CH₂CR²¹═C(R²¹)₂ except when Xis a bond and q is 2; wherein said alkyl and alkylene groups areoptionally substituted with one to three R²⁰ groups; Z¹ is CR²¹═CR²¹,C═C(R²¹)₂, C≡C, or phenylene; wherein said phenylene group is optionallysubstituted with one to three R²⁰ groups; Z² is O, NR^(10A), orS(O)_(y); R¹ is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁵, CO₂R¹¹,C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴, NR²¹S(O)₂R¹¹, S(O)₂NR¹²R¹³, and PO(OR²¹)₂;R² is pyridyl, furyl, thienyl, or a 5-membered heteroaryl groupcontaining 1-3 nitrogen atoms; wherein said heteroaryl group isoptionally substituted with one to three R²⁰ groups; R¹⁰ and R^(10A) ateach occurrence are independently selected from H, C₁-C₆ alkyl, C₆-C₁₀aryl, C(═O)R¹⁵, and S(O)_(y)R¹⁴; wherein said alkyl and aryl groups areoptionally substituted with one to three R²⁰ groups; R¹¹ at eachoccurrence is independently selected from H, and C₁-C₆ alkyl; whereinsaid alkyl is optionally substituted with one to three R²⁰ groups; R¹²and R¹³ at each occurrence are each independently selected from H andC₁-C₆ alkyl, or R¹² and R¹³, together with the nitrogen to which theyare attached, form a 5-6 membered heterocycloalkyl; wherein said alkyland heterocycloalkyl groups are optionally substituted with one to threeR²⁰ groups; R¹⁴ at each occurrence is independently selected from C—C₆alkyl, C₆-C₁₁ aryl, and arylalkyl; wherein said alkyl, aryl andarylalkyl groups are optionally substituted with one to three R²⁰groups; R¹⁵ at each occurrence is independently selected from C₁-C₆alkyl, C₆-C₁₀ aryl, arylalkyl, and heteroaryl; wherein said alkyl, aryl,arylalkyl, and heteroaryl groups are optionally substituted with one tothree R²⁰ groups; R²⁰ at each occurrence is independently selected fromF, Cl, Br, I, OR²¹, OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl,C₃-C₆ spirocycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,arylalkyl, ═O, C(═O)R²², CO₂R²¹, OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²²,NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹C(═S)R²², and S(O)_(y)R²²;R²¹ at each occurrence is independently selected from H and C₁-C₆ alkylR²² at each occurrence is independently selected from C₁-C₆ alkyl andphenyl; R²³ and R²⁴ at each occurrence are each independently selectedfrom H and C₁-C₆ alkyl, or R²³ and R²⁴, together with the nitrogen towhich they are attached, form a 5-6 membered heterocycloalkyl; R²⁵ ateach occurrence is independently the residue of an amino acid after thehydroxyl group of the carboxyl group is removed; m is 0 or 1; n is 0 or1; p is 1, 2, 3, or 4; q is 0, 1, or 2; y is 0, 1, or 2; with thefollowing provisos: 1) when R=H, Y is (C₁-C₆ alkylene)-R¹, and R¹ isCO₂R¹¹ or C(═O)NR¹²R¹³, then the alkylene group must be substituted witha spirocycloalkyl group; 2) when X is not present, then R¹ cannot beNR¹²R¹³; and the stereoisomeric forms, mixtures of stereoisomeric formsor pharmaceutically acceptable salts forms thereof.
 23. The compound ofclaim 22 wherein rings A and B are each independently selected fromphenylene, pyridylene, pyrazinylene, pyrimidinylene, pyrrolylene,pyrazolylene, imidazolylene, furylene, and thienylene.
 24. The compoundof claim 23 wherein X is not present.
 25. The compound of claim 23wherein X is a bond.
 26. The compound of claim 23 wherein R is C₁-C₄alkyl and Y is C₁-C₆ alkylene-R¹.
 27. The compound of claim 23 wherein Ris H and Y is C₁-C₆ alkylene-R¹.
 28. The compound of claims 26 or 27wherein Y is CH₂—R¹.
 29. The compound of claim 23 wherein R¹ is selectedfrom NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, andS(O)₂NR¹²R¹³.
 30. The compound of claim 23 wherein R¹ is C(═O)NR¹²R¹³.31. The compound of claim 23 wherein q is 1, R is H, and Y is C₁-C₆alkylene-C(═C(═O)NR¹²R¹³.
 32. The compound of claim 21 wherein q is 1, Ris H, Y is C₁-C₆ alkylene-R¹, wherein R¹ is selected from NR¹²R¹³,NR²¹C(═O)R¹⁴, C(═O)R¹⁵, C(═O)NR²¹OR¹⁴, NR²¹S(O)₂R¹¹, S(O)₂NR¹²R¹³, andPO(OR²¹)₂.
 33. A compound of formula (IV):

wherein the phenylene rings are each independently optionallysubstituted with one to three R²⁰ groups; X is not present or is a bond;R is H or C₁-C₄ alkyl; Y is selected from: a) C₁-C₆ alkylene-R¹; b)C₁-C₆ alkylene-R²; c) C₁-C₄ alkylene-O(CH₂)_(p)OR²¹, d) CH₂C(OH)(CH₃)₂,CH₂C(CH₃)₂OH, CH₂C(OH)₂CF₃, CH₂C(OH)(C≡CH)₂, or CH₂CH(OH)CH₃, and e)CH₂CR²¹═C(R²¹)₂CH₂CR²¹═C(R²¹)₂ except when X is a bond and q is 2;wherein said alkylene groups optionally substituted with an R²⁰ group;R¹ is selected from pyrrolidinyl, piperidinyl, morpholinyl,NR²¹C(═O)R¹⁴, C(═O)R¹⁵, CO₂R¹¹, C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴,NR²¹S(O)₂R¹¹, S(O)₂NR^(12A)R^(13A), and PO(OR²¹)₂; R² is furyl, thienyl,a 5-membered heteroaryl group containing 1-2 nitrogen atoms, ortriazolyl; wherein said R² groups are optionally substituted with an R²⁰group; R¹¹ at each occurrence is independently C₁-C₆ alkyl; R¹² and R¹³at each occurrence are each independently selected from H and C₁-C₆alkyl, or R¹² and R¹³, together with the nitrogen to which they areattached, form a 5-6 membered heterocycloalkyl; wherein said alkyl andheterocycloalkyl groups are optionally substituted with an R²⁰ group;R^(12A) and R^(13A) at each occurrence are each independently selectedfrom H and C₁-C₆ alkyl; R¹⁴ at each occurrence is independently C₁-C₆alkyl; R¹⁵ at each occurrence is independently selected from C₁-C₆alkyl, and 5-membered heteroaryl; R²⁰ at each occurrence isindependently selected from F, Cl, Br, I, OR²¹, OR²⁵, NR²³R²⁴, NHOH,NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ spirocycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6membered heteroaryl, arylalkyl, ═O, C(═O)R²², CO₂R²¹, OC(═O)R²²,C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═O)R²²,NR²¹C(═S)R²², and S(O)_(y)R²²; R²¹ at each occurrence is independentlyselected from H and C₁-C₆ alkyl; R²² at each occurrence is independentlyselected from C₁-C₆ alkyl, and phenyl; R²³ and R²⁴ at each occurrenceare each independently selected from H and C₁-C₆ alkyl, or R²³ and R²⁴,together with the nitrogen to which they are attached, form a 5-6membered heterocycloalkyl; R²⁵ at each occurrence is independently theresidue of an amino acid after the hydroxyl group of the carboxyl groupis removed; p is 1, 2, 3, or 4; q is 1 or 2; y is 0, 1, or 2; with thefollowing provisos: 1) when R=H, Y is (C₁-C₆ alkylene)-R¹, and R¹ isCO₂R¹¹ or C(═O)NR¹²R¹³, then the alkylene group must be substituted witha spirocycloalkyl group; 2) when X is not present, then R¹ cannot bepyrrolidinyl, piperidinyl, or morpholinyl; and the stereoisomeric forms,mixtures of stereoisomeric forms or pharmaceutically acceptable saltsforms thereof.
 34. The compound of claim 33 wherein Y is selected from:a) C₁-C₄ alkylene-R¹; b) C₁-C₄ alkylene-R²; c) C₁-C₄alkylene-O(CH₂)_(p)OR²¹, d) CH₂C(OH)(CH₃)₂, CH₂C(CH₃)₂OH, CH₂C(OH)₂CF₃,CH₂C(OH)(C≡CH)₂, or CH₂CH(OH)CH₃, and e) CH₂CH═CH₂, or CH₂C(═C)CH₃except when X is a bond and q is 2; wherein said alkylene groups areoptionally substituted with an R²⁰ group; R¹ is selected frompyrrolidinyl, piperidinyl, morpholinyl, NR²¹C(═O)R¹⁴, C(═O)R¹⁵, CO₂R¹¹,C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴, NR²¹S(O)₂R¹¹, S(O)₂NR^(12A)R^(13A), andPO(OR²¹)₂; R² is furyl, thienyl, or triazolonyl; wherein said R² groupsare optionally substituted with an R²⁰ group; R¹¹ at each occurrence isindependently C₁-C₄ alkyl; R¹² and R¹³ at each occurrence are eachindependently selected from H and C₁-C₄ alkyl, optionally substitutedwith C(═O)NR^(12A)R^(13A), or R¹² and R¹³, together with the nitrogen towhich they are attached, form a pyrrolidinyl or piperidinyl ring;R^(12A) and R^(13A) at each occurrence are each independently selectedfrom H and C₁-C₄ alkyl; R¹⁴ at each occurrence is independently C₁-C₄alkyl; R¹⁵ at each occurrence is independently selected from C₁-C₄alkyl, and thienyl; R²⁰ at each occurrence is independently selectedfrom F, Cl, Br, I, OR²¹, OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, ═O,C(═O)R²², CO₂R²¹, C(═O)NR²³R²⁴, and NR²¹C(═O)R²²; R²¹ at each occurrenceis independently selected from H and C₁-C₄ alkyl; R²² at each occurrenceis independently C₁-C₄ alkyl; R²³ and R²⁴ at each occurrence are eachindependently selected from H and C₁-C₄ alkyl, or R²³ and R²⁴, togetherwith the nitrogen to which they are attached, form a 5-6 memberedheterocycloalkyl; R²⁵ at each occurrence is independently the residue ofan amino acid after the hydroxyl group of the carboxyl group is removed;p is 1, 2, 3, or 4; q is 1 or
 2. 35. The compound of claim 1 having astructure of formula (V):

wherein the phenylene rings are each independently optionallysubstituted with one to three R²⁰ groups; X is a bond, O, S(O)_(y),NR¹⁰, C₂ alkylene, or C₂ alkenylene, wherein said alkylene andalkenylene groups are optionally substituted with an R²⁰ group; R is Hor C₁-C₄ alkyl; Y is selected from: a) C₁-C₆ alkylene-R¹; and b)CH₂CR²¹═C(R²¹)₂ except when X is a bond and q is 2; R¹ selected frompyrrolidinyl, piperidinyl, morpholinyl, NR²¹C(═O)R¹⁴, C(═O)NR¹²R¹³, andNR²¹S(O)₂R¹¹; R¹⁰ is independently selected from H, C₁-C₆ alkyl, C₆-C₁₀aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl groups areoptionally substituted with one to three R²⁰ groups; R¹¹ at eachoccurrence is independently C₁-C₆ alkyl; R¹² and R¹³ at each occurrenceare each independently selected from H and C₁-C₆ alkyl, or R¹² and R¹³,together with the nitrogen to which they are attached, form a 5-6membered heterocycloalkyl; wherein said alkyl and heterocycloalkylgroups are optionally substituted with an R²⁰ group; R¹⁴ at eachoccurrence is independently C₁-C₆ alkyl; R²⁰ at each occurrence isindependently selected from F, Cl, Br, I, OR²¹, OR²⁵, NR²³R²⁴, NHOH,NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ spirocycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6membered heteroaryl, arylalkyl, ═O, C(═O)R²², CO₂R²¹, OC(═O)R²²,C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹ CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═O)R²²,NR²¹C(═S)R²², and S(O)_(y)R²²; R²¹ at each occurrence is independentlyselected from H and C₁-C₆ alkyl; R²² at each occurrence is independentlyselected from C₁-C₆ alkyl, and phenyl; R²³ and R²⁴ at each occurrenceare each independently selected from H and C₁-C₆ alkyl, or R²³ and R²⁴,together with the nitrogen to which they are attached, form a 5-6membered heterocycloalkyl; R²⁵ at each occurrence is independently theresidue of an amino acid after the hydroxyl group of the carboxyl groupis removed; y is 0, 1, or 2; with the following proviso: 1) when R=H andY is (C₁-C₆ alkylene)-C(═O)NR¹²R¹³, then the alkylene group must besubstituted with a spirocycloalkyl group; and the stereoisomeric forms,mixtures of stereoisomeric forms or pharmaceutically acceptable saltsforms thereof.
 36. The compound of claim 35 wherein X is a bond; R isC₁-C₄ alkyl, Y is C₁-C₆ alkyl-C(═O)NR¹²R¹³.
 37. The compound of claim 35wherein X is a bond; R is H, Y is C₁-C₆ alkyl-R¹, and R¹ is selectedfrom pyrrolidinyl, piperidinyl, morpholinyl, NR²¹C(═O)R¹⁴, orNR²¹S(O)₂R¹¹.
 38. The compound of claim 35 wherein X is a bond and Y isCH₂CR²¹═C(R²¹)₂ CH₂CR²¹═C(R²¹)₂.
 39. The compound of claim 38 wherein Yis CH₂CH═CH₂, or CH₂C(═C)CH₃.
 40. The compound of claim 35 wherein thephenylene rings are each independently optionally substituted with oneto three R²⁰ groups; q is 1; X is a bond; Y is selected from: a) C₁-C₄alkylene-R¹; and b) CH₂CH═CH₂, or CH₂C(═C)CH₃ except when X is a bondand q is 2; R¹ is selected from pyrrolidinyl, piperidinyl, morpholinyl,NR²¹C(═O)R¹⁴, C(═O)NR¹²R¹³, and NR²¹S(O)₂R¹¹; R¹¹ at each occurrence isindependently C₁-C₄ alkyl; R¹² and R¹³ at each occurrence are eachindependently selected from H and C₁-C₄ alkyl, optionally substitutedwith C(═O)NR^(12A)R^(13A), or R¹² and R¹³, together with the nitrogen towhich they are attached, form a pyrrolidinyl or piperidinyl ring;R^(12A) and R^(13A) at each occurrence are each independently selectedfrom H and C₁-C₄ alkyl; R¹⁴ at each occurrence is independently C₁-C₄alkyl; R²⁰ at each occurrence is independently selected from F, Cl, Br,I, OR²¹, OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, ═O, C(═O)R²², CO₂R²¹,C(═O)NR²³R²⁴, and NR²¹C(═O)R²²; R²¹ at each occurrence is independentlyselected from H and C₁-C₄ alkyl; R²² at each occurrence is independentlyC₁-C₄ alkyl; R²³ and R²⁴ at each occurrence are each independentlyselected from H and C₁-C₄ alkyl, or R²³ and R²⁴, together with thenitrogen to which they are attached, form a 5-6 memberedheterocycloalkyl; R²⁵ at each occurrence is independently the residue ofan amino acid after the hydroxyl group of the carboxyl group is removed.41. The compound of claim 1 having a structure of formula (VI):

wherein Ar¹ and Ar² are each independently phenyl optionally substitutedwith one to three R²⁰ groups; R is H or C₁-C₄ alkyl; Y is selected from:a) C₁-C₆ alkylene-R¹; b) C₁-C₆ alkylene-R²; c) C₁-C₆alkylene-O(CH₂)_(p)OR²¹, and d) CH₂C(OH)(CH₃)₂, CH₂C(CH₃)₂OH,CH₂C(OH)₂CF₃, CH₂C(OH)(C≡CH)₂, or CH₂CH(OH)CH₃; R¹ is selected fromC(═O)R¹⁵, CO₂R¹¹, C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴, S(O)₂NR^(12A)R^(13A), andPO(OR²¹)₂; R² is furyl, thienyl, or triazolyl; wherein said R² groupsare optionally substituted with an R²⁰ group; R¹¹ at each occurrence isindependently C₁-C₆ alkyl; R¹² and R¹³ at each occurrence are eachindependently selected from H and C₁-C₆ alkyl, or R¹² and R¹³, togetherwith the nitrogen to which they are attached, form a 5-6 memberedheterocycloalkyl; R^(12A) and R^(13A) at each occurrence are eachindependently selected from H and C₁-C₆ alkyl; R¹⁴ at each occurrence isindependently C₁-C₆ alkyl; R¹⁵ at each occurrence is independentlyselected from C₁-C₆ alkyl, and 5-membered heteroaryl; R²⁰ at eachoccurrence is independently selected from F, Cl, Br, I, OR²¹, OR²⁵,NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ spirocycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl,phenyl, 5 or 6 membered heteroaryl, arylalkyl, ═O, C(═O)R²², CO₂R²¹,OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²² NR²¹CO₂R²², OC(═O)NR²³R²⁴,NR²¹C(═O)R²², NR²C(═S)R²², and S(O)_(y)R²²; R²¹ at each occurrence isindependently selected from H and C₁-C₆ alkyl; R²² at each occurrence isindependently selected from C₁-C₆ alkyl, and phenyl; R²³ and R²⁴ at eachoccurrence are each independently selected from H and C₁-C₆ alkyl, orR²³ and R²⁴, together with the nitrogen to which they are attached, forma 5-6 membered heterocycloalkyl; R²⁵ at each occurrence is independentlythe residue of an amino acid after the hydroxyl group of the carboxylgroup is removed; p is 1, 2, 3, or 4; y is 0, 1, or 2; with thefollowing provisos: 1) when R=H, Y is (C₁-C₆ alkylene)-R¹, and R¹ isCO₂R¹¹ or C(═O)NR¹²R¹³, then the alkylene group must be substituted witha spirocycloalkyl group; and the stereoisomeric forms, mixtures ofstereoisomeric forms or pharmaceutically acceptable salts forms thereof.42. The compound of claim 41 wherein R is C₁-C₄ alkyl, and Y is C₁-C₆alkyl-C(═C(═O)NR¹²R¹³.
 43. The compound of claim 41 wherein R is H, andY is C₁-C₆ alkyl-R¹, wherein said alkyl is substituted withspirocycloalkyl, and R¹ is CO₂R¹¹ or C(═O)NR¹²R¹³.
 44. The compound ofclaim 43 wherein R¹ is C(═O)NR¹²R¹³.
 45. The compound of claim 41wherein R¹ is selected from C(═O)R¹⁵, C(═O)NR²¹OR¹⁴,S(O)₂NR^(12A)R^(13A), and PO(OR²¹)₂.
 46. The compound of claim 41wherein Y is C₁-C₆ alkylene-O(CH₂)_(p)OR²¹.
 47. The compound of claim 41wherein Y is CH₂C(OH)(CH₃)₂, CH₂C(CH₃)₂OH, CH₂C(OH)₂CF₃,CH₂C(OH)(C≡CH)₂, or CH₂CH(OH)CH₃.
 48. The compound of claim 41 whereinAr¹ and Ar² are each independently phenyl optionally substituted withone to three R²⁰ groups; R is H or C₁-C₄ alkyl; Y is selected from: a)C₁-C₄ alkylene-R¹; b) C₁-C₄ alkylene-R²; c) CH₂CH₂O(CH₂)₂OCH₃, and d)CH₂C(OH)(CH₃)₂, CH₂C(CH₃)₂OH, CH₂C(OH)₂CF₃, CH₂C(OH)(C≡H)₂, orCH₂CH(OH)CH₃, R¹ is selected from C(═O)R¹⁵, CO₂R¹¹, C(═O)NR¹²R¹³,C(═O)NR²¹OR¹⁴, S(O)₂NR^(12A)R^(13A), and PO(OR²¹)₂; R² is furyl,thienyl, or triazolonyl; R¹¹ at each occurrence is independently C₁-C₄alkyl; R¹² and R¹³ at each occurrence are each independently selectedfrom H and C₁-C₄ alkyl; R^(12A) and R^(13A) at each occurrence are eachindependently selected from H and C₁-C₄ alkyl; R¹⁴ at each occurrence isindependently C₁-C₄ alkyl; R¹⁵ at each occurrence is independentlyselected from C₁-C₄ alkyl, and thienyl; R²⁰ at each occurrence isindependently selected from F, Cl, Br, I, OR²¹, OR²⁵, N²³R²⁴, NHOH, NO₂,CN, CF₃, C₃-C₆ spirocycloalkyl, ═O, C(═O)R²², CO₂R²¹, C(═O)NR²³R²⁴, andNR²¹C(═O)R²²; R²¹ at each occurrence is independently selected from Hand C₁-C₄ alkyl; R²² at each occurrence is independently C₁-C₄ alkyl;R²³ and R²⁴ at each occurrence are each independently selected from Hand C₁-C₄ alkyl, or R²³ and R²⁴, together with the nitrogen to whichthey are attached, form a 5-6 membered heterocycloalkyl; R²⁵ at eachoccurrence is independently the residue of an amino acid after thehydroxyl group of the carboxyl group is removed; with the followingproviso: 1) when R=H, Y is (C₁-C₄ alkylene)-R¹, and R¹ is CO₂R¹¹ orC(═O)NR¹²R¹³, then the alkylene group must be substituted with aspirocycloalkyl group.
 49. The compound of claim 48 wherein R is H. 50.The compound of claim 48 wherein R¹ selected from C(═O)R¹⁵,C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴, S(O)₂NR^(12A)R^(13A) and PO(OR²¹)₂.
 51. Thecompound of claim 48 wherein Y is C₁-C₄ alkylene-R¹.
 52. A compoundselected in accordance with Table
 1. 53. A compound selected inaccordance with Table
 2. 54. A method of treating excessive sleepinessassociated with narcolepsy, obstructive sleep apnea or shift workdisorder; Parkinson's disease; Alzheimer's disease; attention deficitdisorder; attention deficit hyperactivity disorder; depression; orfatigue in a subject in need thereof comprising administering to saidsubject a therapeutically effective amount of a compound of formula (A):

wherein rings A and B, together with the carbon atoms to which they areattached, are each independently selected from: a) a 6-membered aromaticcarbocyclic ring in which from 1 to 3 carbon atoms may be replaced byhetero atoms selected from oxygen, nitrogen and sulfur; and b) a5-membered aromatic carbocyclic ring in which either: i) one carbon atommay be replaced with an oxygen, nitrogen, or sulfur atom; ii) two carbonatoms may be replaced with a sulfur and a nitrogen atom, an oxygen and anitrogen atom, or two nitrogen atoms; or iii) three carbon atoms may bereplaced with three nitrogen atoms, one oxygen and two nitrogen atoms,or one sulfur and two nitrogen atoms; wherein said rings are optionallysubstituted with one to three R²⁰ groups; X is not present, is a bond,O, S(O)_(y), NR¹⁰, C₂ alkylene, C₂₋₃ alkenylene, C(═O), C(R²¹)₂NR¹⁰,C(R²¹)═N, N═C(R²¹), C(═O)N(R¹⁰), or NR¹⁰C(═O); wherein said alkylene andalkenylene groups are optionally substituted with one to three R²⁰groups; R is H, C₁-C₆ alkyl, C₆-C₁₀ aryl, 5-6 membered heteroaryl, C₃-C₇cycloalkyl, or 3-7 membered heterocycloalkyl; with the proviso that Rcannot be H when R¹ is C(═O)NR¹²R¹³; Y is C₁-C₉ alkylene-R¹, wherein oneor two carbon atoms can be replaced by one or two O, NR¹⁰, or S(O)_(y)groups, or a carbon atom can be replaced by a C₆-C₁₀ arylene, 5-10membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 memberedheterocycloalkylene group; C₂-C₆ alkenylene-R¹; or C₂-C₆ alkynylene-R¹;wherein said alkylene, alkenylene, alkynylene, arylene, heteroarylene,cycloalkylene, and heterocycloalkylene groups are optionally substitutedwith one to three R²⁰ groups; R¹ is selected from H, NR¹²R¹³,NR²¹C(═O)R¹⁴, C(═O)R¹⁵, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═O)NR²¹OR¹⁴,C(═NR¹¹)NR¹²R¹³, NR²¹S(O)₂R¹¹, S(O)₂NR¹²R¹³, NR²¹S(O)₂NR¹²R¹³, andPO(OR²¹)₂; R¹⁰ and R^(10A) at each occurrence are independently selectedfrom H, C₁-C₆ alkyl, C₆-C₁₀ aryl, C(═O)R¹⁵, and S(O)_(y)R¹⁴; whereinsaid alkyl and aryl groups are optionally substituted with one to threeR²⁰ groups; R¹¹ at each occurrence is independently selected from H, andC₁-C₆ alkyl; wherein said alkyl is optionally substituted with one tothree R²⁰ groups; R¹² and R¹³ at each occurrence are each independentlyselected from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, togetherwith the nitrogen to which they are attached, form a 3-7 memberedheterocycloalkyl ring; wherein said alkyl and aryl groups andheterocycloalkyl ring are optionally substituted with one to three R²⁰groups; R¹⁴ at each occurrence is independently selected from C₁-C₆alkyl, C₆-C₁₀ aryl, and arylalkyl; wherein said alkyl, aryl andarylalkyl groups are optionally substituted with one to three R²⁰groups; R¹⁵ at each occurrence is independently selected from C₁-C₆alkyl, C₆-C₁₀ aryl, arylalkyl, and heteroaryl; wherein said alkyl, aryl,arylalkyl, and heteroaryl groups are optionally substituted with one tothree R²⁰ groups; R²⁰ at each occurrence is independently selected fromF, Cl, Br, I, OR²¹, OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl,C₃-C₆ spirocycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,arylalkyl, ═O, C(═O)R²², CO₂R²¹, OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²²,NR²¹ CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹C(═S)R²², and S(O)_(y)R²²;R²¹ at each occurrence is independently selected from H and C₁-C₆ alkyl;R²² at each occurrence is independently selected from C₁-C₆ alkyl, andC₆-C₁₀ aryl; R²³ and R²⁴ at each occurrence are each independentlyselected from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, togetherwith the nitrogen to which they are attached, form a 3-7 memberedheterocycloalkyl ring; R²⁵ at each occurrence is independently theresidue of an amino acid after the hydroxyl group of the carboxyl groupis removed; q is 0, 1, or 2; y is 0, 1, or 2; with the proviso that whenR=H and Y is (C₁-C₆ alkylene)-C(═O)NR¹²R¹³, then the alkylene group mustbe substituted with a spirocycloalkyl group; and the stereoisomericforms, mixtures of stereoisomeric forms or pharmaceutically acceptablesalts forms thereof.
 55. The method of claim 54 wherein the compound isadministered for the treatment of excessive sleepiness associated withnarcolepsy, obstructive sleep apnea or shift work disorder.
 56. Apharmaceutical composition comprising a compound of claim 1 in admixturewith one or more pharmaceutically acceptable excipients.